Publications by authors named "Yanfang Xu"

58 Publications

Inhibitory G protein-mediated modulation of slow delayed rectifier potassium channels contributes to increased susceptibility to arrhythmogenesis in aging heart.

Heart Rhythm 2021 Sep 15. Epub 2021 Sep 15.

Department of Pharmacology, Hebei Medical University; The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province. Electronic address:

Background: Slow delayed rectifier potassium current (I) is an important component of repolarization reserve during sympathetic nerve excitement. However, little is known about age-related functional changes of I and its involvement in age-dependent arrhythmogenesis.

Objective: To investigate age-related alteration of the I response to β-adrenergic receptor (βAR) activation.

Methods: Dunkin-Hartley guinea pigs were used. Whole-cell patch-clamp recording was used to record K currents. Optical mapping of membrane potential was performed in ex vivo heart.

Results: There was no difference in I density in ventricular cardiomyocytes between young and old guinea pigs. However, in contrast to I potentiation in young hearts, isoproterenol (ISO) evoked an acute inhibition on I in a concentration-dependent manner in old guinea pig hearts. The βAR antagonist, but not βAR antagonist, reversed the inhibitory response. Preincubation of cardiomyocytes with the inhibitory G protein (Gi) inhibitor pertussis toxin (PTX) also reversed the inhibitory response. In HEK293 cells co-transfected with cloned I channel and βAR, ISO enhanced the current but reduced it when cells were co-transfected with Gi2, and PTX restored the ISO-induced excitatory response. Moreover, in aging cardiomyocytes, Gβγ inhibitor gallein, PLC inhibitor U73122, or protein kinase C inhibitor Bis-1 prevented the reduction of I by ISO. Furthermore, cardiac-specific Gi2 overexpression in young guinea pigs predisposed the heart to ventricular tachyarrhythmias. PTX pretreatment protected the hearts from ventricular arrhythmias.

Conclusion: βAR activation acutely induces an inhibitory I response in aging guinea pig hearts through βAR-Gi signaling, which contributes to increased susceptibility to arrhythmogenesis in aging hearts.
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http://dx.doi.org/10.1016/j.hrthm.2021.09.014DOI Listing
September 2021

Effect of smartphone app on post-traumatic stress disorder in COVID-19 convalescent patients: A protocol for systematic review and meta-analysis.

Medicine (Baltimore) 2021 Apr;100(14):e25479

Department of Pneumology, The Sixth People's Hospital of KunShan, KunShan 215321, Jiangsu Province, China.

Background: The outbreak of Coronavirus Disease 2019 (COVID-19) seriously affects humans' health worldwide physically and mentally. Studies revealed that the prevalence of post-traumatic stress disorder (PTSD) increased under this condition. PTSD can change the structure of patients' central nervous system, and increase the risk of anxiety or depression, thus greatly affecting the quality of patients' life and their families. PTSD is preventable, and the effects of early prevention are better. Non-drug intervention can prevent or reduce the psychological sequelae after hospitalization, help patients understand the experience during hospitalization, and be beneficial to their psychological rehabilitation. Whether smartphone app based intervention can be an alternative therapy for PTSD in terms of COVID-19 convalescent patients is still controversial. Therefore, we conducted a meta-analysis and systematic review to evaluate the effects of smartphone app based intervention on PTSD in COVID-19 convalescent patients, so as to provide some guidance for clinical application.

Methods: The literatures that are related to the smartphone app based intervention and PTSD in COVID-19 convalescent patients from inception to February 2021 will be searched. The following databases are our focused areas: ClinicalTrials.gov, Cochrane Central Register of Controlled Trials repositories, PubMed, EmBase, and Web of Science databases. According to the inclusion and exclusion criteria, 2 investigators would independently screen the literature extract data and evaluate the risk of bias in the included studies. Meta-analysis was performed with RevMan5.3 software.

Results: The results of this meta-analysis will be submitted to a peer-reviewed journal for publication.

Conclusion: The conclusion of our study could provide evidence for the judgment of whether smartphone app based intervention is an effective intervention on PTSD in COVID-19 convalescent patients.

Prospero Registration Number: CRD42021240340.
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http://dx.doi.org/10.1097/MD.0000000000025479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036085PMC
April 2021

Cardiac hERG K Channel as Safety and Pharmacological Target.

Handb Exp Pharmacol 2021 ;267:139-166

Department of Pharmacology, Hebei Medical University, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei, China.

The human ether-á-go-go related gene (hERG, KCNH2) encodes the pore-forming subunit of the potassium channel responsible for a fast component of the cardiac delayed rectifier potassium current (I). Outward I is an important determinant of cardiac action potential (AP) repolarization and effectively controls the duration of the QT interval in humans. Dysfunction of hERG channel can cause severe ventricular arrhythmias and thus modulators of the channel, including hERG inhibitors and activators, continue to attract intense pharmacological interest. Certain inhibitors of hERG channel prolong the action potential duration (APD) and effective refractory period (ERP) to suppress premature ventricular contraction and are used as class III antiarrhythmic agents. However, a reduction of the hERG/I current has been recognized as a predominant mechanism responsible for the drug-induced delayed repolarization known as acquired long QT syndromes (LQTS), which is linked to an increased risk for "torsades de pointes" (TdP) ventricular arrhythmias and sudden cardiac death. Many drugs of different classes and structures have been identified to carry TdP risk. Hence, assessing hERG/I blockade of new drug candidates is mandatory in the drug development process according to the regulatory agencies. In contrast, several hERG channel activators have been shown to enhance I and shorten the APD and thus might have potential antiarrhythmic effects against pathological LQTS. However, these activators may also be proarrhythmic due to excessive shortening of APD and the ERP.
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http://dx.doi.org/10.1007/164_2021_455DOI Listing
January 2021

High-Performance Structural Supercapacitors Based on Aligned Discontinuous Carbon Fiber Electrodes and Solid Polymer Electrolytes.

ACS Appl Mater Interfaces 2021 Mar 8;13(10):11774-11782. Epub 2021 Mar 8.

Department of Mechanical Engineering, University of Delaware, Newark, Delaware 19716, United States.

This paper presents an investigation of the potential to use aligned discontinuous carbon fiber dry prepregs as electrodes in structural supercapacitors (SSCs). The high fiber-matrix interfacial bonding of the structural composite was achieved by adopting a solid polymer electrolyte, consisting of poly(vinylidene), lithium triflate, and epoxy. Processing of the SSC was carried out via dip-coating of the polymer electrolyte and then cured using a vacuum bag. The electrochemical performance of the SSCs was measured before and after mechanical loading. The microstructures of the SSCs as-fabricated and damaged under flexural loading were identified by μ-CT imaging. An SSC with a specific capacitance of 0.128 mF/cm (11.62 mF/g), a flexural strength of 47.49 MPa, and a flexural modulus of 8.48 GPa has been achieved, demonstrating significant improvements in mechanical properties over those of SSCs based on woven carbon fiber fabric-based electrodes. The mechanical behavior of the supercapacitors was evaluated by both quasi-static and cyclic flexural loading tests. The excellent electrochemical stability of the supercapacitors was validated by a capacitance retention of above 96% under galvanostatic charge-discharge cycling tests. The knowledge gained in this work will benefit future research in the optimization of SSC performance.
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http://dx.doi.org/10.1021/acsami.0c19550DOI Listing
March 2021

GSDME-mediated pyroptosis promotes inflammation and fibrosis in obstructive nephropathy.

Cell Death Differ 2021 Aug 4;28(8):2333-2350. Epub 2021 Mar 4.

Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.

Renal tubular cell (RTC) death and inflammation contribute to the progression of obstructive nephropathy, but its underlying mechanisms have not been fully elucidated. Here, we showed that Gasdermin E (GSDME) expression level and GSDME-N domain generation determined the RTC fate response to TNFα under the condition of oxygen-glucose-serum deprivation. Deletion of Caspase-3 (Casp3) or Gsdme alleviated renal tubule damage and inflammation and finally prevented the development of hydronephrosis and kidney fibrosis after ureteral obstruction. Using bone marrow transplantation and cell type-specific Casp3 knockout mice, we demonstrated that Casp3/GSDME-mediated pyroptosis in renal parenchymal cells, but not in hematopoietic cells, played predominant roles in this process. We further showed that HMGB1 released from pyroptotic RTCs amplified inflammatory responses, which critically contributed to renal fibrogenesis. Specific deletion of Hmgb1 in RTCs alleviated caspase11 and IL-1β activation in macrophages. Collectively, our results uncovered that TNFα/Casp3/GSDME-mediated pyroptosis is responsible for the initiation of ureteral obstruction-induced renal tubule injury, which subsequentially contributes to the late-stage progression of hydronephrosis, inflammation, and fibrosis. This novel mechanism will provide valuable therapeutic insights for the treatment of obstructive nephropathy.
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http://dx.doi.org/10.1038/s41418-021-00755-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329275PMC
August 2021

Ultralight, hydrophobic, sustainable, cost-effective and floating kapok/microfibrillated cellulose aerogels as speedy and recyclable oil superabsorbents.

J Hazard Mater 2021 03 4;406:124758. Epub 2020 Dec 4.

College of Textiles, Donghua University, Shanghai 201620, China. Electronic address:

Cellulose aerogels achieve excellent absorption of waste oil and organic pollutant, which has received lots of attention recently. It is still a big challenge to obtain aerogels with both high cost-effectiveness and advanced oil absorption performance, since it is a time-consuming, and environmentally unfriendly process to obtain cellulose, compared with direct usage of natural fibers. In this manuscript, we develop highly porous and hydrophobic kapok/microfibrillated cellulose (MFC) aerogels with a dual-scale hierarchically porous structure at micro-level as cost-effective, sustainable, and floating superabsorbents via simple vacuum freeze-drying and surface modification. Kapok, a natural hollow fiber, has been recently considered as a new sustainable resource for oil cleanup. By partially replacing MFC with chopped kapok fibers in MFC aerogels (MMAs), the resultant kapok/MFC aerogels (KCAs) exhibit ultralow density (5.1 mg/cm), ultrahigh porosity (99.58%) and hydrophobicity (140.1°) leading to advanced oil sorption (130.1 g/g) that is 25.3% higher than that of MMAs. In addition, these KCAs can rapidly and selectively absorb waste oil from oil-water mixture with ultrahigh absorption ability of 104-190.1 g/g, which is comparable to other environmentally unfriendly and high-cost aerogels. Furthermore, the KCAs own excellent reusability and sustainability. These benefits enable the KCAs a suitable alternative to clean oil spills.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124758DOI Listing
March 2021

Electroless deposition of silver nanoparticles on cellulose nanofibrils for electromagnetic interference shielding films.

Carbohydr Polym 2020 Dec 14;250:116915. Epub 2020 Aug 14.

College of Sciences, Research Center of Nano Science and Technology, Shanghai University, Shanghai 200444, PR China; Dehong Autonomous Prefecture Institute of Sugar Industry, Yunnan 678400, PR China. Electronic address:

High-efficient electromagnetic interference (EMI) shielding films were successfully fabricated by electroless deposition of silver nanoparticles (AgNPs) on polydopamine (PDA) functionalized cellulose nanofibrils (CNFs) as building blocks according to a pressured-extrusion film-forming process. PDA was first functionalized on CNFs by oxidative self-polymerization of dopamine (DA) to synthesize [email protected], on which AgNPs were electrolessly deposited. The obtained [email protected]@AgNPs composite films served as tightly-connected conductive network, so as to significantly improve the whole electrical conductivity of the EMI shielding films. Utilizing CNFs as green and soft matrix, the fabricated [email protected]@AgNPs EMI films show an outstanding mechanical enduring performance. The [email protected]@AgNPs films with weight ratios of CNFs:AgNO = 1:24 exhibited superb electrical conductivity of 1,000,000 S m and remarkable EMI shielding effectiveness of 93.8 dB at 8.2 GHz in X band. This work provides a simple methodology to achieve surface metallization of insulating fibers to supersede traditional metals for highly efficient EMI shielding applications.
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http://dx.doi.org/10.1016/j.carbpol.2020.116915DOI Listing
December 2020

Risk factors for renal failure and short-term prognosis in patients with spontaneous intracerebral haemorrhage complicated by acute kidney injury.

BMC Nephrol 2020 07 29;21(1):311. Epub 2020 Jul 29.

Department of Nephrology, First Affiliated Hospital, Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China.

Background: Although acute kidney injury (AKI) is a known risk factor for adverse clinical outcomes in patients with spontaneous intracerebral haemorrhage (SICH), little is known about the predisposing factors that contribute to renal failure and short-term prognosis in the setting of SICH already complicated by AKI. In this study, we aimed to identify the renal failure factors in SICH patents with AKI.

Methods: Five hundred forty-three patients with SICH complicated by differential severities of AKI who were admitted to the First Affiliated Hospital of Fujian Medical University from January 2016 to December 2018 were retrospectively studied. Logistic regression and receiver operator characteristic (ROC) curve analysis were performed to determine the best predictive and discriminative variables. Multivariate Cox regression analysis was performed to identify prognostic factors for renal recovery.

Results: In the multivariable adjusted model, we found that hypernatremia, metabolic acidosis, elevated serum creatine kinase, hyperuricaemia, proteinuria, and the use of colloids and diuretics were all independent risk factors for the occurrence of stage 3 AKI in SICH patients. The area under the curve analysis indicated that hypernatremia and hyperuricaemia were predictive factors for stage 3 AKI, and the combination of these two parameters increased their predictability for stage 3 AKI. Kaplan-Meier survival curves revealed that the renal recovery rate in SICH patients with stages 1 and 2 AKI was significantly higher than that in SICH patients with stage 3 AKI. Multivariate Cox regression analysis suggested that hypernatremia and the occurrence of stage 3 AKI are predictors for poor short-term renal recovery.

Conclusions: These findings illustrate that hypernatremia and hyperuricaemia represent potential risk factors for the occurrence of stage 3 AKI in SICH patients. Those patients with hypernatremia and stage 3 AKI were associated with a poor short-term prognosis in renal recovery.
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http://dx.doi.org/10.1186/s12882-020-01949-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391601PMC
July 2020

42 °C heat stress pretreatment protects human melanocytes against 308-nm laser-induced DNA damage in vitro.

Lasers Med Sci 2020 Oct 30;35(8):1801-1809. Epub 2020 May 30.

Department of Dermatology, The Air Force Medical Center of Air Force Military Medical University of Chinese PLA, Beijing, China.

Vitiligo is a common depigment of skin disorder due to loss of functional melanocytes. Recently, the phototherapy with a 308-nm xenon-chloride excimer laser (UVB laser) is wildly used in vitiligo treatment. However, excessive UVB will induce photo-damage and photo-carcinogenesis in melanocytes. Previous studies revealed a protective effect of heat on UVB-induced melanocyte damage. In this study, we combined heat stress pretreatment with UVB to evaluate whether heat stress pretreatment has an ameliorative effect on UVB-induced damage. Human primary melanocytes (HMCs) were cultured and irradiated with a 308-nm laser with/without heat treatment. MTT assay, apoptosis analysis, and comet assay were conducted to monitor the damage of HMCs. Western blot and immunofluorescence staining were performed to assess the expression and subcellular localization of HSP70. HMCs heated at 42 °C for 1 h exhibit no cytotoxicity. Furthermore, preheat treatment attenuated the UVB laser-induced injury, reduced the DNA damage, and attenuated the cell apoptosis. The level and the localization of HSP70 determined the protective effects against UVB-induced DNA damage. Combining preheat treatment with a 308-nm xenon-chloride excimer laser would be a potential therapeutic method not only promotes the repigment of vitiligo but also reduces the UVB-induced photo-damage.
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http://dx.doi.org/10.1007/s10103-020-03012-3DOI Listing
October 2020

RIPK3 collaborates with GSDMD to drive tissue injury in lethal polymicrobial sepsis.

Cell Death Differ 2020 09 9;27(9):2568-2585. Epub 2020 Mar 9.

Department of Nephrology, First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.

Sepsis is a systemic inflammatory disease causing life-threatening multi-organ dysfunction. Accumulating evidences suggest that two forms of programmed necrosis, necroptosis and pyroptosis triggered by the pathogen component lipopolysaccharide (LPS) and inflammatory cytokines, play important roles in the development of bacterial sepsis-induced shock and tissue injury. Sepsis-induced shock and tissue injury required receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL) phosphorylation, caspase11 activation and gasdermin D (GSDMD) cleavage. However, the synergistic effect of necroptosis and pyroptosis in the pathological progress of sepsis remains elusive. In this study, we found that blockage of both necroptosis and pyroptosis (double deletion of Ripk3/Gsdmd or Mlkl/Gsdmd) resulted in accumulative protection against septic shock, systemic blood clotting and multi-organ injury in mice. Bone marrow transplantation confirmed that necroptosis and pyroptosis in both myeloid and nonmyeloid cells are indispensable in the progression of sepsis-induced multi-organ injury. Both RIPK3 and GSDMD signaling collaborated to amplify necroinflammation and tissue factor release in macrophages and endothelial cells, which led to tissue injury. Furthermore, cell death induced by inflammatory cytokines and high-mobility group box 1 could be prevented by double ablation of Ripk3/Gsdmd or Mlkl/Gsdmd, suggesting that a positive feedback loop interconnecting RIPK3/MLKL and GSDMD machinery and inflammation facilitated sepsis progression. Collectively, our findings demonstrated that RIPK3-mediated necroptosis and GSDMD-mediated pyroptosis collaborated to amply inflammatory signaling and enhance tissue injury in the process of sepsis, which may shed new light on two potential targets of combined therapeutic interventions for this highly lethal disorder.
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http://dx.doi.org/10.1038/s41418-020-0524-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429874PMC
September 2020

Saikosaponin a attenuates hyperlipidemic pancreatitis in rats via the PPAR-γ/NF-κB signaling pathway.

Exp Ther Med 2020 Feb 13;19(2):1203-1212. Epub 2019 Dec 13.

Department of Hepatobiliary Surgery, Quzhou People's Hospital, Quzhou, Zhejiang 324000, P.R. China.

The therapeutic effect of saikosaponin a (SSa) on hyperlipidemic pancreatitis (HP) is not completely understood. The aim of the present study was to investigate the therapeutic effect and the underlying mechanism of SSa using a rat model of HP. Following successful establishment of the HP rat model, different doses of SSa (low dose group, 10 mg/kg or high dose group, 20 mg/kg) were administrated. Histopathological examination, the wet/dry (W/D) ratio and myeloperoxidase (MPO) activity of the pancreatic tissues were assessed. The lipid, amylase (AMY), lipase and proinflammatory cytokine profiles in serum, as well as the expression of peroxisome proliferator-activated receptor (PPAR)-γ and the NF-κB signaling pathway-related proteins in pancreatic tissues were evaluated. The results showed that SSa effectively attenuated pancreatic pathological injury and reduced both the W/D ratio and MPO activity compared to the HP model rats. SSa also improved lipid metabolism by significantly decreasing the serum levels of total cholesterol and triglycerides (P<0.05). Following the administration of SSa, the activity of AMY and lipase, as well as the levels of the proinflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β and IL-6 were reduced, particularly in the high dosage group (P<0.05). Furthermore, SSa activated PPAR-γ expression and suppressed the NF-κB signaling pathway in pancreatic tissues. The present study suggested that SSa attenuated HP in rats by increasing lipid metabolism and inhibiting the release of proinflammatory cytokines via the NF-κB inflammatory pathway. The results from the present study indicated that SSa might be a promising therapeutic agent for the treatment of HP.
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http://dx.doi.org/10.3892/etm.2019.8324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966209PMC
February 2020

Auxiliary subunits control biophysical properties and response to compound NS5806 of the Kv4 potassium channel complex.

FASEB J 2020 01 27;34(1):807-821. Epub 2019 Nov 27.

Department of Pharmacology, Hebei Medical University, Shijiazhuang, China.

Kv4 pore-forming subunits co-assemble with β-subunits including KChIP2 and DPP6 and the resultant complexes conduct cardiac transient outward K current (I). Compound NS5806 has been shown to potentate I in canine cardiomyocytes; however, its effects on I in other species yet to be determined. We found that NS5806 inhibited native I in a concentration-dependent manner (0.1~30 μM) in both mouse ventricular cardiomyocytes and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), but potentiated I in the canine cardiomyocytes. In HEK293 cells co-transfected with cloned Kv4.3 (or Kv4.2) and β-subunit KChIP2, NS5806 significantly increased the peak current amplitude and slowed the inactivation. In contrast, NS5806 suppressed the current and accelerated inactivation of the channels when cells were co-transfected with Kv4.3 (or Kv4.2), KChIP2 and another β-subunit, DPP6-L (long isoform). Western blot analysis showed that DPP6-L was dominantly expressed in both mouse ventricular myocardium and hiPSC-CMs, while it was almost undetectable in canine ventricular myocardium. In addition, low level of DPP6-S expression was found in canine heart, whereas levels of KChIP2 expression were comparable among all three species. siRNA knockdown of DPP6 antagonized the I inhibition by NS5806 in hiPSC-CMs. Molecular docking simulation suggested that DPP6-L may associate with KChIP2 subunits. Mutations of putative KChIP2-interacting residues of DPP6-L reversed the inhibitory effect of NS5806 into potentiation of the current. We conclude that a pharmacological modulator can elicit opposite regulatory effects on Kv4 channel complex among different species, depending on the presence of distinct β-subunits. These findings provide novel insight into the molecular design and regulation of cardiac I. Since I is a potential therapeutic target for treatment of multiple cardiovascular diseases, our data will facilitate the development of new therapeutic I modulators.
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http://dx.doi.org/10.1096/fj.201902010RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972550PMC
January 2020

Downregulation of miR-146a Contributes to Cardiac Dysfunction Induced by the Tyrosine Kinase Inhibitor Sunitinib.

Front Pharmacol 2019 23;10:914. Epub 2019 Aug 23.

Department of Pharmacology, Hebei Medical University, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, China.

The main adverse effect of tyrosine kinase inhibitors, such as sunitinib, is cardiac contractile dysfunction; however, the molecular mechanisms of this effect remain largely obscure. MicroRNAs (miRNAs) are key regulatory factors in both cardiovascular diseases and the tyrosine kinase pathway. Therefore, we analyzed the differential expression of miRNAs in the myocardium in mice after exposure to sunitinib using miRNA microarray. A significant downregulation of miR-146a was observed in the myocardium of sunitinib-treated mice, along with a 20% decrease in left ventricle ejection fraction (LVEF). The downregulation of miR-146a was further validated by RT-qPCR. Among the potential targets of miR-146a, we focused on and , which are closely related to cardiac contractile dysfunction. Results of luciferase reporter assay confirmed that miR-146a directly targeted the 3' untranslated region of and . Significant upregulation of PLN and ANK2 at the mRNA and protein levels was observed in the myocardium of sunitinib-treated mice. Cardiac-specific overexpression of miR-146a prevented the deteriorate effect of SNT on calcium transients, thereby alleviating the decreased contractility of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). SiRNA knockdown of PLN or ANK2 prevented sunitinib-induced suppression of contractility in hiPSC-CMs. Therefore, our and results showed that sunitinib downregulated miR-146a, which contributes to cardiac contractile dysfunction by regulating the downstream targets PLN and ANK2, and that upregulation of miR-146a alleviated the inhibitory effect of SNT on cardiac contractility. Thus, miR-146a could be a useful protective agent against sunitinib-induced cardiac dysfunction.
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http://dx.doi.org/10.3389/fphar.2019.00914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716347PMC
August 2019

Upregulation of phosphoinositide 3-kinase prevents sunitinib-induced cardiotoxicity in vitro and in vivo.

Arch Toxicol 2019 06 25;93(6):1697-1712. Epub 2019 Apr 25.

Department of Pharmacology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China.

Sunitinib (SNT) is a multi-targeted receptor tyrosine kinase inhibitor that has been approved by the FDA for cancer therapy. However, its cardiotoxicity has limited the clinical applicability with no effective therapeutic approach available. As a broadband kinase inhibitor, the function of several kinases that are essential to cardiac function might also be affected by SNT, such as calmodulin-dependent protein kinase (CaMKII), cyclic-AMP-dependent protein kinases (PKA), AMP-activated protein kinase (AMPK), and phosphoinositide 3 kinase (PI3K). In this study, we investigated whether SNT-induced cardiotoxicity could be prevented by blocking SNT-induced alteration in the corresponding signaling pathways. In human induced pluripotent stem cell-derived cardiomyocytes, SNT (0.5-20 µmol/L) inhibited contractility of cardiomyocytes in a concentration-dependent manner, and the inhibitory effect was prevented either by PIP3 (1 µmol/L) application or PI3K overexpression. On the contrary, the CaMKII inhibitor KN-93 (50 nmol/L), PKA inhibitor H89 (1 µmol/L), and AMPK activators metformin (2 mmol/L) and 5-aminoimidazole-4-carboxamide 1-b-D-ribofuranoside (2 mmol/L) presented negligible effects. Oral SNT administration (40 mg/kg/day) in mice progressively decreased the PI3K activity and cardiac function in 2 weeks with a significant decrease in the expression and activity of Cav1.2 and SERCA. Cardiac-specific PI3K overexpression through adeno-associated virus 9-mediated gene delivery in mice prevented SNT-induced reduction in cardiac function, calcium transient, calcium current, and Cav1.2 expression. In summary, our data indicate that increased PI3K activity is protective against SNT-induced calcium mishandling and contractile dysfunction. Cardiac-specific PI3K activation could be an effective therapeutic approach to treat SNT cardiotoxicity in patients with cancer.
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http://dx.doi.org/10.1007/s00204-019-02448-zDOI Listing
June 2019

Don't trick me twice!

Kidney Int 2019 04;95(4):736-738

Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany. Electronic address:

Chemotherapy-induced nephrotoxicity limits the success of cancer therapy. Landau et al. now describe a mechanism by which a first dose of cisplatin renders the kidney sensitive to necroptosis mediated by a second dose. Unresolved injury and sustained necrosis, therefore, may represent a pathophysiological means of transition from acute kidney injury to chronic kidney disease.
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http://dx.doi.org/10.1016/j.kint.2018.12.004DOI Listing
April 2019

Bone Marrow Mesenchymal Stem Cells Accelerate the Morphological and Functional Recovery of Neovaginas.

Artif Organs 2018 Dec 23;42(12):1206-1215. Epub 2018 Oct 23.

Department of Pharmacology, Hebei Medical University, Shijiazhuang, China.

Vaginal reconstruction is the main solution to the problem of sexuality and gender roles for patients with no vagina. A tissue-engineered vagina may be the best choice. However, many defects have been found in neovaginas reconstructed with a graft only. In this study, we investigated whether a stem cell-seeded graft would accelerate the morphological and functional recovery of neovaginas. CM-DiI-labeled bone marrow mesenchymal stem cell (MSC)-seeded small intestinal submucosa (SIS) (SIS+MSCs group) was used for vaginal reconstruction in a rat model; unseeded SIS (SIS group) was used as a control. The neovaginas of each group were harvested at 4 and 12 weeks after surgery. Morphological analyses were performed using hematoxylin and eosin (H&E) staining and immunohistochemical staining for α-smooth muscle actin (SMA), protein gene product 9.5(PGP9.5), and CD34. Functional recovery was evaluated using an organ bath study. The role of MSCs in the neovagina was analyzed by immunofluorescence and molecular biology methods. At the 4th week, a regenerated epithelium covered the whole neovagina in both groups. A small amount of smooth muscle regeneration was found in the neovagina. Up to the 12th week, nerve fibers appeared. There were more smooth muscle and nerve fibers, along with better contractility, in the neovagina of the SIS+MSCs group. Further study showed that the MSCs differentiated into smooth muscles at the 4th week. A higher microvessel density (MVD) and more vascular endothelial growth factor (VEGF) were found in the neovagina of the SIS+MSCs group. In short, MSCs accelerate the structural and functional recovery of the neovagina.
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http://dx.doi.org/10.1111/aor.13297DOI Listing
December 2018

RIPK3-MLKL-mediated necroinflammation contributes to AKI progression to CKD.

Cell Death Dis 2018 08 29;9(9):878. Epub 2018 Aug 29.

Department of Nephrology, First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.

Necroptosis predominates functionally over apoptosis in the pathophysiology of renal ischemia-reperfusion injury (IRI). Inhibition of the core components of the necroptotic pathway-receptor-interacting protein kinase 1 (RIPK1), RIPK3 or mixed lineage kinase domain-like protein (MLKL) reduced renal injury after ischemia/reperfusion (IR). Necrosis can initiate inflammation, which enhances necrosis in a positive feedback loop, subsequently leading to triggering more inflammation, termed as necroinflammation. However, the mechanisms underlying necroinflammation driven by renal tubular cell necroptosis in progression of AKI to CKD are still largely unknown. Here we showed that the upregulated expression and interactions between RIPK3 and MLKL induced necroptosis of renal proximal tubular cells and contributed to NLRP3 inflammasome activation under the conditions of IRI. Gene deletion of Ripk3 or Mlkl ameliorated renal tubular cell necroptosis, macrophage infiltration and NLRP3 inflammasome activation with a reduction in caspase-1 activation and maturation of IL-1β, and then finally reduced interstitial fibrogenesis in the long term after IRI. Bone marrow chimeras confirmed that RIPK3-MLKL-dependent necroptosis is responsible for the initiation of the early renal injury after IRI, and then necroptosis triggered NLRP3 inflammasome activation, which subsequently accelerates necroptosis and triggers more inflammation in an auto-amplification loop. These data indicate that necroinflammation driven by RIPK3-MLKL-dependent necroptosis plays a crucial role in the progression of IRI to CKD.
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http://dx.doi.org/10.1038/s41419-018-0936-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115414PMC
August 2018

Utility of the JT Peak Interval and the JT Area in Determining the Proarrhythmic Potential of QT-Shortening Agents.

J Cardiovasc Pharmacol Ther 2019 03 9;24(2):160-171. Epub 2018 Aug 9.

Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei, China.

Drug-induced long QT increases the risk of ventricular tachyarrhythmia known as (TdP). Many biomarkers have been used to predict TdP. At present, however, there are few biomarkers for arrhythmias induced by QT-shortening drugs. The objective of the present study was to identify the best biomarkers for predicting arrhythmias caused by the 4 potassium channel openers ICA-105574, NS-1643, R-L3, and pinacidil. Our results showed that, at higher concentrations, all 4 potassium channel openers induced ventricular tachycardia (VT) and ventricular fibrillation (VF) in Langendorff-perfused guinea pig hearts, but not in rabbit hearts. The electrocardiography parameters were measured including QT/QTc, JT peak, Tp-e interval, JT area, short-term beat-to-beat QT interval variability (STV), and index of cardiac electrophysiological balance (iCEB). We found that the potassium channel openers at test concentrations shortened the QT/QTc and the JT peak interval and increased the JT area. Nevertheless, even at proarrhythmic concentrations, they did not always change STV, Tp-e, or iCEB. Receiver operating characteristic curve analysis showed that the JT peak interval representing the early repolarization phase and the JT area reflecting the dispersion of ventricular repolarization were the best predictors of VT/VF. Action potential recordings in guinea pig papillary muscle revealed that except for pinacidil, the potassium channel openers shortened APD in a concentration-dependent manner. They also evoked early or delayed afterdepolarizations at fast pacing rates. Patch-clamp recordings in guinea pig ventricular cardiomyocytes showed that the potassium channel openers enhanced the total outward currents during the early phase of action potential repolarization, especially at proarrhythmic concentrations. We concluded that the JT peak interval and the JT area are surrogate biomarkers identifying the risk of proarrhythmia associated with the administration of QT-shortening agents. The acceleration of early-phase repolarization and the increased dispersion of ventricular repolarization may contribute to the occurrence of arrhythmias.
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http://dx.doi.org/10.1177/1074248418791999DOI Listing
March 2019

Protein kinase C epsilon mediates the inhibition of angiotensin II on the slowly activating delayed-rectifier potassium current through channel phosphorylation.

J Mol Cell Cardiol 2018 03 13;116:165-174. Epub 2018 Feb 13.

Department of Pharmacology, Hebei Medical University, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang 050017, China. Electronic address:

The slowly activating delayed rectifier K current (I) is one of the main repolarizing currents in the human heart. Evidence has shown that angiotensin II (Ang II) regulates I through the protein kinase C (PKC) pathway, but the related results are controversial. This study was designed to identify PKC isoenzymes involved in the regulation of I by Ang II and the underlying molecular mechanism. The whole-cell patch-clamp technique was used to record I in isolated guinea pig ventricular cardiomyocytes and in human embryonic kidney (HEK) 293 cells co-transfected with human KCNQ1/KCNE1 genes and Ang II type 1 receptor genes. Ang II inhibited I in a concentration-dependent manner in native cardiomyocytes. A broad PKC inhibitor Gö6983 (not inhibiting PKCε) and a selective cPKC inhibitor Gö6976 did not affect the inhibitory action of Ang II. In contrast, the inhibition was significantly attenuated by PKCε-selective peptide inhibitor εV1-2. However, direct activation of PKC by phorbol 12-myristate 13-acetate (PMA) increased the cloned human I in HEK293 cells. Similarly, the cPKC peptide activator significantly enhanced the current. In contrast, the PKCε peptide activator inhibited the current. Further evidence showed that PKCε knockdown by siRNA antagonized the Ang II-induced inhibition on KCNQ1/KCNE1 current, whereas knockdown of cPKCs (PKCα and PKCβ) attenuated the potentiation of the current by PMA. Moreover, deletion of four putative phosphorylation sites in the C-terminus of KCNQ1 abolished the action of PMA. Mutation of two putative phosphorylation sites in the N-terminus of KCNQ1 and one site in KCNE1 (S102) blocked the inhibition of Ang II. Our results demonstrate that PKCε isoenzyme mediates the inhibitory action of Ang II on I and by phosphorylating distinct sites in KCNQ1/KCNE1, cPKC and PKCε isoenzymes produce the contrary regulatory effects on the channel. These findings have provided new insight into the molecular mechanism underlying the modulation of the KCNQ1/KCNE1 channel.
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http://dx.doi.org/10.1016/j.yjmcc.2018.02.010DOI Listing
March 2018

Different protein kinase C isoenzymes mediate inhibition of cardiac rapidly activating delayed rectifier K current by different G-protein coupled receptors.

Br J Pharmacol 2017 Dec 7;174(23):4464-4477. Epub 2017 Nov 7.

Department of Pharmacology, Hebei Medical University, Shijiazhuang, China; The Key Laboratory of New Drug Pharmacology and Toxicology, Shijiazhuang, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, China.

Background And Purpose: Elevated angiotensin II (Ang II) and sympathetic activity contributes to a high risk of ventricular arrhythmias in heart disease. The rapidly activating delayed rectifier K current (I ) carried by the hERG channels plays a critical role in cardiac repolarization, and decreased I is involved in increased cardiac arrhythmogenicity. Stimulation of α -adrenoreceptors or angiotensin II AT receptors is known to inhibit I via PKC. Here, we have identified the PKC isoenzymes mediating the inhibition of I by activation of these two different GPCRs.

Experimental Approach: The whole-cell patch-clamp technique was used to record I in guinea pig cardiomyocytes and HEK293 cells co-transfected with hERG and α -adrenoreceptor or AT receptor genes.

Key Results: A broad spectrum PKC inhibitor Gö6983 (not inhibiting PKCε), a selective cPKC inhibitor Gö6976 and a PKCα-specific inhibitor peptide, blocked the inhibition of I by the α -adrenoreceptor agonist A61603. However, these inhibitors did not affect the reduction of I by activation of AT receptors, whereas the PKCε-selective inhibitor peptide did block the effect. The effects of angiotensin II and the PKCε activator peptide were inhibited in mutant hERG channels in which 17 of the 18 PKC phosphorylation sites were deleted, whereas a deletion of the N-terminus of the hERG channels selectively prevented the inhibition elicited by A61603 and the cPKC activator peptide.

Conclusions And Implications: Our results indicated that inhibition of I by activation of α -adrenoreceptors or AT receptors were mediated by PKCα and PKCε isoforms respectively, through different molecular mechanisms.
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http://dx.doi.org/10.1111/bph.14049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715974PMC
December 2017

Protein kinase D at the Golgi controls NLRP3 inflammasome activation.

J Exp Med 2017 Sep 17;214(9):2671-2693. Epub 2017 Jul 17.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France

The inflammasomes are multiprotein complexes sensing tissue damage and infectious agents to initiate innate immune responses. Different inflammasomes containing distinct sensor molecules exist. The NLRP3 inflammasome is unique as it detects a variety of danger signals. It has been reported that NLRP3 is recruited to mitochondria-associated endoplasmic reticulum membranes (MAMs) and is activated by MAM-derived effectors. Here, we show that in response to inflammasome activators, MAMs localize adjacent to Golgi membranes. Diacylglycerol (DAG) at the Golgi rapidly increases, recruiting protein kinase D (PKD), a key effector of DAG. Upon PKD inactivation, self-oligomerized NLRP3 is retained at MAMs adjacent to Golgi, blocking assembly of the active inflammasome. Importantly, phosphorylation of NLRP3 by PKD at the Golgi is sufficient to release NLRP3 from MAMs, resulting in assembly of the active inflammasome. Moreover, PKD inhibition prevents inflammasome autoactivation in peripheral blood mononuclear cells from patients carrying NLRP3 mutations. Hence, Golgi-mediated PKD signaling is required and sufficient for NLRP3 inflammasome activation.
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http://dx.doi.org/10.1084/jem.20162040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584123PMC
September 2017

Cisplatin-induced necroptosis in TNFα dependent and independent pathways.

Cell Signal 2017 02 6;31:112-123. Epub 2017 Jan 6.

Central Laboratory, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China.

Cisplatin is a chemotherapeutic drug for treatment of many solid tumors. It has been shown to induce apoptosis and/or necrosis in different types of cancer cells. However, the underlying mechanisms remain elusive. In this study, we provide evidences that cisplatin induces necroptosis in receptor-interacting protein 3 (RIP3)-expressing cell lines, but not in cell lines lacking RIP3 protein expression. Deficiency of core components of necroptotic pathway, RIP1, RIP3, or mixed lineage kinase domain-like protein (MLKL) blocked cisplatin-induced cell death in L929 cells. This phenomenon is dependent on RIP1/RIP3/MLKL necrosome formation and translocation to mitochondria-associated membrane (MAM), but only partially via autocrine production of tumor necrosis factor α (TNFα). Moreover, we demonstrate that the mitochondrial permeability transition pore opening (mPTP) opening and reactive oxygen species (ROS) generation is a critical downstream event of the formation of necrosome in cisplatin-induced necroptosis, which is TNFα independent. Deficiency of cyclophilin-D (CypD) partially reduced cisplatin-induced cell death, indicating CypD mediated-mPTP opening plays an important role during cisplatin-induced necroptosis. Both deletion of CypD and TNFα completely blocked cisplatin-induced cell death, suggesting that cisplatin could induce necroptosis through TNFα dependent and independent pathway. These findings provide new insight into the molecular mechanisms underlying cisplatin-induced necroptosis.
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http://dx.doi.org/10.1016/j.cellsig.2017.01.004DOI Listing
February 2017

Circulating neuregulin 4 levels are inversely associated with subclinical cardiovascular disease in obese adults.

Sci Rep 2016 11 7;6:36710. Epub 2016 Nov 7.

Department of Endocrinology and Diabetes, The First Affiliated Hospital of Xiamen University, Xiamen, China.

Neuregulin 4 (Nrg4) has been identified as a new secreted adipokine that may protect against development of obesity and metabolic disorders. However, information is not available regarding the association between circulating Nrg4 and subclinical atherosclerosis in humans. We measured serum Nrg4 in 485 obese adult subjects (aged 40 years or older) who had the measurement of carotid intima-media thickness (CIMT) recruited from the community. Individuals with increased CIMT and carotid plaque had lower levels of circulating Nrg4 than controls (p < 0.05). The risks of increased CIMT and atherosclerotic plaque were significantly decreased by 28% and 31% [OR (95% CI): 0.72 (0.53-0.98) and 0.69 (0.50-0.96), respectively], adjusting for age, sex, current smoking, alcohol consumption, physical activity, BMI, systolic BP, fasting glucose, total cholesterol, HDL-c, HOMA-IR, and body fat. Importantly, individuals in the lowest quartile of serum Nrg4 were 3.70 times (p < 0.001) more likely to have increased CIMT and 2.06 times (p < 0.05) more likely to have atherosclerotic plaque than those in the highest quartile in multivariable logistic regression analyses. These findings suggest that circulating Nrg4 concentrations are inversely associated with subclinical atherosclerosis in obese adults, and indicating that circulating Nrg4 might play a role in identifying patients at high risk for CVD.
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http://dx.doi.org/10.1038/srep36710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098181PMC
November 2016

Association of circulating neuregulin 4 with metabolic syndrome in obese adults: a cross-sectional study.

BMC Med 2016 10 24;14(1):165. Epub 2016 Oct 24.

Department of Endocrinology and Diabetes, The First Affiliated Hospital of Xiamen University, Teaching Hospital of Fujian Medical University, 55 Zhenhai Road, Xiamen, 361003, China.

Background: Neuregulin 4 (Nrg4) is a secreted adipokine recently identified as playing an important role in modulating systemic energy metabolism and the development of obesity-associated disorders. However, information is not available regarding the association between circulating Nrg4 and risk of metabolic syndrome (MetS) in humans.

Methods: We measured serum Nrg4 in 1212 obese adult subjects (aged 40 years or older), with a waist circumference greater than 90 cm for men or 80 cm for women, recruited from the community.

Results: MetS subjects had lower levels of circulating Nrg4 than healthy controls (P < 0.01). The prevalence of MetS was higher in subjects with lower levels of circulating Nrg4 compared to those with higher values (67.3 % vs. 57.4 %, P < 0.05). Likewise, subjects with low levels of circulating Nrg4 had high prevalence of raised fasting glucose and blood pressure, but there was no association with raised triglycerides and reduced HDL-c. In multivariable logistic regression analyses, increased serum Nrg4 was significantly associated with reduced risk of MetS (OR: 0.603; 95 % CI, 0.439-0.828; P = 0.002), adjusting for age, gender, current smoking, alcohol consumption, physical activity, BMI, systolic blood pressure, fasting glucose, triglyceride, HDL-c, HOMA-IR, and body fat mass; however, such associations with serum Nrg4 were not noted for each component of MetS.

Conclusions: These findings indicate that circulating Nrg4 concentrations are inversely associated with risk of MetS in obese Chinese adults, suggesting that circulating Nrg4 concentrations may be a protective factor in the development of MetS.
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http://dx.doi.org/10.1186/s12916-016-0703-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075753PMC
October 2016

The Necrosome in Acute Kidney Injury.

Semin Nephrol 2016 05;36(3):199-207

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China.

Cell death and inflammation in the proximal tubules are the hallmarks of acute kidney injury (AKI), but the underlying mechanism has not been fully elucidated. Recent evidence has shown that necroptosis, a type of programmed necrosis, plays an important role in AKI. The necrosis-inducing signaling complex is called the necrosome, which contains receptor-interacting protein 1, receptor-interacting protein 3, and mixed lineage kinase domain-like protein. Studies have found that inhibition of the core components of the necroptotic pathway by gene knockout, RNA interference, or a chemical inhibitor diminished proximal tubule damage, showing that necroptosis is a major contributor to AKI. This review focuses on the functional roles of the necrosome in regulating renal tubular cell necroptosis, and the physiological and pathologic roles of necrosome in AKI.
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http://dx.doi.org/10.1016/j.semnephrol.2016.03.007DOI Listing
May 2016

Hepatic fat content is a determinant of metabolic phenotypes and increased carotid intima-media thickness in obese adults.

Sci Rep 2016 Feb 23;6:21894. Epub 2016 Feb 23.

Department of Endocrinology and Diabetes, The First Affiliated Hospital, Xiamen University, Xiamen, China.

Individuals with metabolically healthy obesity (MHO) are at relatively low risk for the development of metabolic abnormalities and subclinical atherosclerosis. This study aims to examine whether hepatic fat accumulation determines metabolic phenotype of obesity and associated with subclinical atherosclerosis. A total of 485 obese adults (aged 40-65 years) who received magnetic resonance spectroscopy were divided into metabolically abnormally obesity (MAO) and MHO groups according to metabolic status. MHO individuals had lower levels of intrahepatic triglyceride (IHTG) content and carotid intima-media thickness (CIMT) than MAO individuals. In multivariable linear regression analyses, IHTG content was independently associated with metabolic syndrome components and CIMT. Based on receiver operating characteristic curve analysis, the IHTG content displayed a higher area under the curve (AUC) for detecting the MAO phenotype (AUC = 0.70, 95%CI = 0.65-0.75) and increased CIMT (AUC = 0.60, 95%CI = 0.54-0.66) than BMI, waist circumference, and body fat percent. MHO individuals were 1.9 times (p < 0.001) more likely to have metabolic syndrome per 1 SD change in IHTG content in multivariable-adjusted models. Likewise, the risk for high CIMT increased 29% per 1 SD change in IHTG content [OR (95% CI):1.29(1.01-1.64)]. These findings suggest that hepatic fat is a potential predictor of metabolically unhealthy obesity phenotype and subclinical atherosclerosis.
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http://dx.doi.org/10.1038/srep21894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763213PMC
February 2016

Biogeographical patterns of biomass allocation in leaves, stems, and roots in China's forests.

Sci Rep 2015 Nov 3;5:15997. Epub 2015 Nov 3.

Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China.

To test whether there are general patterns in biomass partitioning in relation to environmental variation when stand biomass is considered, we investigated biomass allocation in leaves, stems, and roots in China's forests using both the national forest inventory data (2004-2008) and our field measurements (2011-2012). Distribution patterns of leaf, stem, and root biomass showed significantly different trends according to latitude, longitude, and altitude, and were positively and significantly correlated with stand age and mean annual precipitation. Trade-offs among leaves, stems, and roots varied with forest type and origin and were mainly explained by stand biomass. Based on the constraints of stand biomass, biomass allocation was also influenced by forest type, origin, stand age, stand density, mean annual temperature, precipitation, and maximum temperature in the growing season. Therefore, after stand biomass was accounted for, the residual variation in biomass allocation could be partially explained by stand characteristics and environmental factors, which may aid in quantifying carbon cycling in forest ecosystems and assessing the impacts of climate change on forest carbon dynamics in China.
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http://dx.doi.org/10.1038/srep15997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630587PMC
November 2015

Bone marrow mesenchymal stem cells could acquire the phenotypes of epithelial cells and accelerate vaginal reconstruction combined with small intestinal submucosa.

Cell Biol Int 2015 Nov 7;39(11):1225-33. Epub 2015 Jul 7.

Department of Pharmacology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050000, China.

Grafting material for vaginal reconstruction commonly includes the bowel, peritoneum, skin, and amniotic membrane. Bone marrow mesenchymal stem cells (MSCs) have the potential of multilineage differentiation into a variety of cells and have been widely explored in tissue engineering. In the current study, we examined whether MSCs could be differentiated to vaginal epithelial cells (VECs) upon co-culturing with VECs. We also examined whether Wnt/β-catenin signaling pathway is implicated in such differentiation. Co-culture of MSCs with VECs using a transwell insert system (with no direct contact) induced the expression of VECs marker AE1/AE3 in MSCs. MSCs combined with small intestinal submucosa (SIS) scaffold were implanted in place of the native vagina in rats to observe the implications for vaginal reconstruction in vivo. Anatomic repair of neovagina was assessed by histological staining for H/E and Masson's Trichrome. GSK-3β and β-catenin, main members of Wnt/β-catenin signaling pathway, in MSCs were increased upon co-culturing with VECs. Exposure of co-cultured MSCs to a Wnt/β-catenin signaling activator, lithium chloride (LiCl, 20 µM) increased phosphorylated GSK-3β and β-catenin and enhanced expression of AE1/AE3. In vivo-grafted cells displayed significant matrix infiltration and expressed epithelial markers in neovagina. These findings suggest that MSCs could acquire the phenotype of VECs when co-cultured with VECs, possibly via activation of Wnt/β-catenin signaling. MSCs provide an alternative cell source for potential use in vaginal tissue engineering.
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http://dx.doi.org/10.1002/cbin.10495DOI Listing
November 2015

Aldosterone down-regulates the slowly activated delayed rectifier potassium current in adult guinea pig cardiomyocytes.

Br J Pharmacol 2015 Dec 15;172(23):5596-608. Epub 2015 May 15.

Department of Pharmacology, Hebei Medical University, The Key Laboratory of New Drug Pharmacology and Toxicology, Shijiazhuang, Hebei, China.

Background And Purpose: There is emerging evidence that the mineralocorticoid hormone aldosterone is associated with arrhythmias in cardiovascular disease. However, the effect of aldosterone on the slowly activated delayed rectifier potassium current (IK s ) remains poorly understood. The present study was designed to investigate the modulation of IK s by aldosterone.

Experimental Approach: Adult guinea pigs were treated with aldosterone for 28 days via osmotic pumps. Standard glass microelectrode recordings and whole-cell patch-clamp techniques were used to record action potentials in papillary muscles and IK s in ventricular cardiomyocytes.

Key Results: The aldosterone-treated animals exhibited a prolongation of the QT interval and action potential duration with a higher incidence of early afterdepolarizations. Patch-clamp recordings showed a significant down-regulation of IK s density in the ventricular myocytes of these treated animals. These aldosterone-induced electrophysiological changes were fully prevented by a combined treatment with spironolactone, a mineralocorticoid receptor (MR) antagonist. In addition, in in vitro cultured ventricular cardiomyocytes, treatment with aldosterone (sustained exposure for 24 h) decreased the IK s density in a concentration-dependent manner. Furthermore, a significant corresponding reduction in the mRNA/protein expression of IKs channel pore and auxiliary subunits, KCNQ1 and KCNE1 was detected in ventricular tissue from the aldosterone-treated animals.

Conclusions And Implications: Aldosterone down-regulates IK s by inhibiting the expression of KCNQ1 and KCNE1, thus delaying the ventricular repolarization. These results provide new insights into the mechanism underlying K(+) channel remodelling in heart disease and may explain the highly beneficial effects of MR antagonists in HF.
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http://dx.doi.org/10.1111/bph.13163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667866PMC
December 2015

A Role for Tubular Necroptosis in Cisplatin-Induced AKI.

J Am Soc Nephrol 2015 Nov 18;26(11):2647-58. Epub 2015 Mar 18.

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China;

Cell death and inflammation in the proximal tubules are the hallmarks of cisplatin-induced AKI, but the mechanisms underlying these effects have not been fully elucidated. Here, we investigated whether necroptosis, a type of programmed necrosis, has a role in cisplatin-induced AKI. We found that inhibition of any of the core components of the necroptotic pathway-receptor-interacting protein 1 (RIP1), RIP3, or mixed lineage kinase domain-like protein (MLKL)-by gene knockout or a chemical inhibitor diminished cisplatin-induced proximal tubule damage in mice. Similar results were obtained in cultured proximal tubular cells. Furthermore, necroptosis of cultured cells could be induced by cisplatin or by a combination of cytokines (TNF-α, TNF-related weak inducer of apoptosis, and IFN-γ) that were upregulated in proximal tubules of cisplatin-treated mice. However, cisplatin induced an increase in RIP1 and RIP3 expression in cultured tubular cells in the absence of cytokine release. Correspondingly, overexpression of RIP1 or RIP3 enhanced cisplatin-induced necroptosis in vitro. Notably, inflammatory cytokine upregulation in cisplatin-treated mice was partially diminished in RIP3- or MLKL-deficient mice, suggesting a positive feedback loop involving these genes and inflammatory cytokines that promotes necroptosis progression. Thus, our data demonstrate that necroptosis is a major mechanism of proximal tubular cell death in cisplatin-induced nephrotoxic AKI.
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http://dx.doi.org/10.1681/ASN.2014080741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625668PMC
November 2015
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