Publications by authors named "Zhengang Zhang"

38 Publications

Association of central obesity with hepatocellular carcinoma in patients with chronic hepatitis B receiving antiviral therapy.

Aliment Pharmacol Ther 2021 Aug 22;54(3):329-338. Epub 2021 Jun 22.

Guangzhou, China.

Background: Obesity is typically associated with metabolic dysfunction, but its impact on hepatocellular carcinoma (HCC) remains unclear in patients with chronic hepatitis B (CHB).

Aim: To study the effect of obesity on HCC development in patients with CHB receiving antiviral therapy.

Methods: We included patients from a Chinese multicentre, prospective, observational, treated CHB cohort in this study. General obesity was evaluated by body-mass index (BMI). Central obesity was evaluated by waist circumference, waist-to-hip ratio and waist-to-height ratio.

Results: A total of 5754 nucleos(t)ide analogue treated patients were enrolled in the analysis. The 5-year cumulative incidence of HCC was 2.9%. Waist-to-height ratio performed better in predicting HCC development than BMI, waist circumference or waist-to-hip ratio. Patients with central obesity (defined as waist-to-height ratio >0.5) had significantly higher 5-year incidence of HCC than those without central obesity in the overall population (3.9% vs 2.1%, hazard ratio [HR]: 2.06, P = 0.0001) and 745 propensity score matched pairs (4.7% vs 2.3%, HR: 2.04, P = 0.026), respectively. Besides cirrhosis status and aMAP HCC risk score, central obesity was also independently associated with HCC risk (HR: 1.63, P = 0.013). Waist-to-height ratio gain within 1 year was associated with a significantly higher HCC risk with an adjusted HR value of 1.88 (95% confidence interval: 1.12-3.13, P = 0.017).

Conclusions: Central obesity, evaluated by the waist-to-height ratio, was associated with a twofold increase in HCC risk among CHB patients receiving antiviral treatment, highlighting the important role of abnormal metabolic function in the progression of liver disease.
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http://dx.doi.org/10.1111/apt.16469DOI Listing
August 2021

Insights into the Bond Behavior and Mechanical Properties of Hafnium Carbide under High Pressure and High Temperature.

Inorg Chem 2021 Jan 19;60(2):515-524. Epub 2020 Nov 19.

School of Mathematics and Physics, China University of Geosciences (Wuhan), Wuhan 430074, P. R. China.

Hafnium carbide (HfC) is a potential candidate of ultrahigh-temperature ceramics (UHTCs) and has attracted significantly widespread interest in recent years. Here, we have synthesized high-purity HfC samples with NaCl-type structure by using a high-pressure solid-solid reaction. The structural stability, equation of state, plastic deformation, yield strength, and bonding properties under high pressure are investigated by a series of in situ high-pressure synchrotron-radiation angle-dispersive X-ray diffraction experiments combined with first-principles calculations. The yield strength of HfC (∼18 GPa) is obtained from analyzing the plastic deformation behavior under high pressure. In addition, we have successfully prepared bulk HfC ceramics with high density using a high-pressure and high-temperature method. The synthesized sample possesses a desirable Vickers hardness of 24.2 GPa and an excellent fracture toughness of 5.0 MPa·m. The present results offer insights into the achievable application of HfC ceramics under extreme conditions and provide a powerful guide for the further design and synthesis of other high-performance UHTCs.
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http://dx.doi.org/10.1021/acs.inorgchem.0c02800DOI Listing
January 2021

Early identification of carotid vulnerable plaque in asymptomatic patients.

BMC Cardiovasc Disord 2020 10 1;20(1):429. Epub 2020 Oct 1.

Department of Cardiology, The Affiliated Hospital of Yangzhou University, Yangzhou University, 45# Taizhou road, Yangzhou, 225000, Jiangsu Province, China.

Background: This study was to explore the influencing factors of atherosclerotic plaque formation and stability in patients with asymptomatic carotid atherosclerotic plaques, so as to identify the vulnerable plaques at early stage, and then find high-risk group of cardio-cerebrovascular events for early clinical intervention to reduce related mortality and disability.

Methods: A total of 302 enrolled patients with asymptomatic carotid atherosclerotic plaques were divided into 3 groups based on the results of carotid artery color Doppler ultrasound: atherosclerotic unstable plaque (UP) group, atherosclerotic stable plaque (SP) group, and control group without plaques. Serum markers were measured by ELISA. χ test, t test, Pearson correlation analysis, and Logistic multivariate regression analysis were used in the analysis, and P < 0.05 was considered statistically significant.

Results: It revealed that high MMP-9, LOX-1and YKL-40 were independent risk factors for unstable plaque formation. The area under the curve (AUC) of serum markers combined with MMP-9, LOX-1 and YKL-40 was 0.850, with sensitivity 87.67%, specificity 81.13%, and diagnostic accuracy 84.92%, which was significantly better than the individual diagnostic efficacy of other three factors. The accuracy rate of Crouse Plaque Score (CPS) in the diagnosis of vulnerable plaques was 61.90%, the 10-year ICVD diagnosis accuracy rate was 56.75%, and the diagnostic accuracy of serum markers was significantly better than CPS and 10-year ICVD.

Conclusion: Noninvasive cervical color Doppler ultrasound combined with serum markers MMP-9, LOX-1 and YKL-40 have significant early recognition effect on asymptomatic carotid vulnerable plaque patients.
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http://dx.doi.org/10.1186/s12872-020-01709-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528473PMC
October 2020

aMAP risk score predicts hepatocellular carcinoma development in patients with chronic hepatitis.

J Hepatol 2020 12 21;73(6):1368-1378. Epub 2020 Jul 21.

Department of Infectious Diseases, First Hospital of Shanxi Medical University, Taiyuan, China.

Background & Aims: Hepatocellular carcinoma (HCC) is the leading cause of death in patients with chronic hepatitis. In this international collaboration, we sought to develop a global universal HCC risk score to predict the HCC development for patients with chronic hepatitis.

Methods: A total of 17,374 patients, comprising 10,578 treated Asian patients with chronic hepatitis B (CHB), 2,510 treated Caucasian patients with CHB, 3,566 treated patients with hepatitis C virus (including 2,489 patients with cirrhosis achieving a sustained virological response) and 720 patients with non-viral hepatitis (NVH) from 11 international prospective observational cohorts or randomised controlled trials, were divided into a training cohort (3,688 Asian patients with CHB) and 9 validation cohorts with different aetiologies and ethnicities (n = 13,686).

Results: We developed an HCC risk score, called the aMAP score (ranging from 0 to 100), that involves only age, male, albumin-bilirubin and platelets. This metric performed excellently in assessing HCC risk not only in patients with hepatitis of different aetiologies, but also in those with different ethnicities (C-index: 0.82-0.87). Cut-off values of 50 and 60 were best for discriminating HCC risk. The 3- or 5-year cumulative incidences of HCC were 0-0.8%, 1.5-4.8%, and 8.1-19.9% in the low- (n = 7,413, 43.6%), medium- (n = 6,529, 38.4%), and high-risk (n = 3,044, 17.9%) groups, respectively. The cut-off value of 50 was associated with a sensitivity of 85.7-100% and a negative predictive value of 99.3-100%. The cut-off value of 60 resulted in a specificity of 56.6-95.8% and a positive predictive value of 6.6-15.7%.

Conclusions: This objective, simple, reliable risk score based on 5 common parameters accurately predicted HCC development, regardless of aetiology and ethnicity, which could help to establish a risk score-guided HCC surveillance strategy worldwide.

Lay Summary: In this international collaboration, we developed and externally validated a simple, objective and accurate prognostic tool (called the aMAP score), that involves only age, male, albumin-bilirubin and platelets. The aMAP score (ranged from 0 to 100) satisfactorily predicted the risk of hepatocellular carcinoma (HCC) development among over 17,000 patients with viral and non-viral hepatitis from 11 global prospective studies. Our findings show that the aMAP score had excellent discrimination and calibration in assessing the 5-year HCC risk among all the cohorts irrespective of aetiology and ethnicity.
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http://dx.doi.org/10.1016/j.jhep.2020.07.025DOI Listing
December 2020

Mechanical properties of tantalum carbide from high-pressure/high-temperature synthesis and first-principles calculations.

Phys Chem Chem Phys 2020 Mar;22(9):5018-5023

Centre for Science at Extreme Conditions and SUPA, School of Physics and Astronomy, The University of Edinburgh, Edinburgh EH9 3FD, UK.

As a member of the refractory metal carbide family of materials, TaC is a promising candidate for ultra-high temperature ceramics (UHTC) with desirable mechanical strength. TaC sample quality and therefore mechanical properties are strongly dependent on synthesis method, and atomistic origins of mechanical failure are difficult to assign. Here, we have successfully synthesized high quality densified TaC samples at 5.5 GPa and 1400 °C using the high pressure and high temperature (HPHT) sintering method, with Vickers hardness determined to be 20.9 GPa. First-principles calculations based on the recently developed strain-stress method show that the ideal indentation strength of TaC is about 23.3 GPa in the (11[combining macron]0)[001] direction, in excellent agreement with experimental results. The detailed indentation shear deformation analysis and structural snapshots from the calculations indicate that the slip dislocations of TaC layers are the main structural deformation mode during the Vickers indentation process, and that the strong directional Ta-C bonds are responsible for the high mechanical strength of TaC. HPHT synthesis is shown to produce TaC samples with superior strength, and together with accurate first-principles calculations offers crucial insights for rational design and synthesis of novel and advanced UHTC materials.
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http://dx.doi.org/10.1039/c9cp06819hDOI Listing
March 2020

Exploring Physical Properties of Tantalum Carbide at High Pressure and Temperature.

Inorg Chem 2020 Feb 12;59(3):1848-1852. Epub 2019 Dec 12.

School of Mathematics and Physics , China University of Geosciences (Wuhan) , Wuhan 430074 , P. R. China.

Among the transition metal carbides, tantalum carbide (TaC) has gained significant interest due to its attractive mechanical and electronic properties. Here, we have performed high pressure and high temperature (HPHT) measurements on the physical properties of TaC under 5.5 GPa and rhythmically increased temperatures from 1000 to 1500 °C. The microscopic deviatoric strain, Vickers hardness, fracture toughness, grain size, and microstructures are characterized by X-ray diffraction (XRD), scanning electronic microscopy (SEM), transmission electron microscopy (TEM), and microhardness tests. The results reveal that the HPHT sintering causes the densification, which increases the mechanical properties of TaC. At 5.5 GPa and 1300 °C, the Vickers hardness, fracture toughness, relative density, and Young's modulus of TaC are 21.0 GPa, 7.4 MPa m, 457 GPa, and 97.7%, respectively, which are in good agreement with available experimental and theoretical values. It is found that the mechanical properties of TaC are highly impressible to the microstructures and microscopic deviatoric stress. Our cadent HPHT sintering technique will provide powerful guidance for further synthesis and design of other novel ultrahigh temperature ceramics (UHTCs).
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http://dx.doi.org/10.1021/acs.inorgchem.9b03055DOI Listing
February 2020

A New Mechanism of Dynamic Phase Transformations in An Isothermal Forged Beta-Gamma Intermetallic Alloy.

Materials (Basel) 2019 Aug 30;12(17). Epub 2019 Aug 30.

Department of Mechanical and Industrial Engineering, Ryerson University, Toronto, ON M5B 2K3, Canada.

A new mechanism of dynamic phase transformations of α ↔ γ in an isothermally forged γ-TiAl-based alloy that occur simultaneously during a short-term exposure at 1000 °C is identified in this study. In the heating process, γ phase significantly decreases through a phase transformation of γ → α, while new γ lamellae are precipitated in the interior of equiaxed grains of α phase through a phase transformation of α → γ. The reasons for the presence of these two inverse phase transformations α ↔ γ occurring simultaneously are discussed.
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http://dx.doi.org/10.3390/ma12172787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747777PMC
August 2019

[Hypoxia enhances proliferation and migration of mouse pulmonary artery smooth muscle cells in vitro].

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2019 Jan;35(1):39-45

Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou 225012, China. *Corresponding author, E-mail:

Objective To establish and improve a primary culture method of mouse pulmonary artery smooth muscle cells (PASMCs), and explore the effects of different hypoxic conditions on the proliferation, migration, and apoptosis of PASMCs. Methods Under sterile conditions, pulmonary arteries were isolated from male mice and PASMCs were obtained using an improved method of tissue piece inoculation through digesting with trypsin. Cell morphology was observed under an inverted phase-contrast microscope, and cell growth curve was plotted by cell counting. Immunofluorescence staining of α-smooth muscle actin (α-SMA) was used to assess the cell type and purity of PASMCs. The effect of different oxygen concentrations on the proliferation of PASMCs was detected by CCK-8 assay. Under hypoxia, the migration ability of PASMCs was detected by scratch wound assay, and the expression of BAX protein was detected by Western blot analysis. Results The cells tended to be long spindle and grew in the typical "peak-valley" mode. Cells were confluent after 9 days and the growth curve presented with a sigmoidal shape. The positive expression rate of α-SMA was 96%. Compared with the normoxic group, the proliferation and migration of PASMCs significantly increased under hypoxia at all time points, and the cell proliferation and migration was the most significant under the condition of 10 mL/L oxygen content. Moreover, BAX protein level of the cells was significantly reduced under hypoxia in a time-dependent manner. Conclusion The primary PASMCs with high purity and activity can be obtained by enzyme digestion and tissue mass adherent method. PASMCs exhibit higher proliferation, increased migration, and declined apoptosis under 10 mL/L oxygen concentration.
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January 2019

Elongin B is a binding partner of the male germ cell nuclear speckle protein sperm-associated antigen 16S (SPAG16S) and is regulated post-transcriptionally in the testis.

Reprod Fertil Dev 2019 Apr;31(5):962-971

Department of Physiology, Wayne State University, 275E Hancock Street, Detroit, MI 48201, USA; and Department of Obstetrics and Gynecology, Wayne State University, 275E Hancock Street, Detroit, MI 48201, USA; and Corresponding author. Email:

In this study we identified Elongin B, a regulatory subunit of the trimeric elongation factor Elongin ABC, which increases the overall rate of elongation by RNA polymerase II, as a major binding partner of sperm-associated antigen 16S (SPAG16S), a component of nuclear speckles. Nuclear speckles are nuclear subcompartments involved in RNA maturation. Previously, we showed that SPAG16S is essential for spermatogenesis. In the present study, a specific antibody against mouse Elongin B was generated and reacted with a protein with the predicted size of Elongin B in the testis; immunofluorescence staining revealed that the Elongin B was located in the nuclei and residual bodies. In round spermatids, Elongin B was colocalised with splicing factor SC35 (SC35), a marker of nuclear speckles. During the first wave of spermatogenesis, Elongin B transcripts were initially detected at Postnatal Day (PND) 8, and levels were greatly increased afterwards. However, Elongin B protein was only found from PND30, when germ cells progressed through spermiogenesis. Polysomal gradient analysis of Elongin B transcripts isolated from adult mouse testes revealed that most of the Elongin B mRNA was associated with translationally inactive, non-polysomal ribonucleoproteins. An RNA electrophoretic mobility shift assay demonstrated that the 3' untranslated region of the Elongin B transcript was bound by proteins present in testis but not liver extracts. These findings suggest that post-transcriptional regulation of Elongin B occurs in the testis, which is a common phenomenon during male germ cell development. As a major binding partner of SPAG16S, Elongin B may play an important role in spermatogenesis by modulating RNA maturation.
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http://dx.doi.org/10.1071/RD18303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254889PMC
April 2019

Effects of triptolide and methotrexate nanosuspensions on left ventricular remodeling in autoimmune myocarditis rats.

Int J Nanomedicine 2019 29;14:851-863. Epub 2019 Jan 29.

Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA,

Purpose: This study was carried out to investigate the effects of a triptolide (TP) nanosuspension and methotrexate (MTX) nanosuspension on left ventricular remodeling and cardiac function for autoimmune myocarditis (EAM) in rats. The regulating effects on inflammatory cytokines in the peripheral serum and related mechanisms are also discussed.

Methods: First, TP and MTX were prepared as a nanosuspension, and the EAM model was successfully established in rats with cardiac myosin. Then, the effect of TP and MTX suspensions was tested in an EAM model.

Results: Results revealed that both TP and MTX suspensions could reduce the degree of myocardial fibrosis and delay the remodeling process of the left ventricle which could further improve cardiac function. Finally, it was found that inflammatory cytokines in the peripheral serum were regulated by the nonspecific immune system and the inhibition of nuclear factor-κB signaling might have partly occurred due to this mechanism.

Conclusion: In summary, this study provided a complete foundation for EAM therapy of profound clinical relevance.
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http://dx.doi.org/10.2147/IJN.S191267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361222PMC
March 2019

Change in lipid profile and risk of new-onset atrial fibrillation in patients with chronic heart failure: A 3-year follow-up observational study in a large Chinese hospital.

Medicine (Baltimore) 2018 Sep;97(39):e12485

School of Basic Medical Sciences, Nanjing Medical University, Nanjing, PR China.

In chronic heart failure (CHF), new-onset atrial fibrillation (AF) is associated with increased morbidity and mortality. We aimed to evaluate the influence of dyslipidemia on the incidence of new-onset AF in patients with CHF.In this single-center observational study, 308 patients with CHF and no history of AF were followed-up for 3 years. Of the 291 patients who attended the 1-year follow-up, 78 had developed AF (AF group; 10 deaths), while 213 had not (sinus rhythm [SR] group). Changes in lipid profile (ΔTC for total cholesterol and ΔLDLc for low-density lipoprotein cholesterol) were analyzed.The groups differed significantly regarding the decrease in lipid levels from baseline to the 1-year follow-up (AF vs SR: for ΔLDLc, 23.35 vs 7.80 mg/dL, P = .02; for ΔTC, 23.95 vs -2.76 mg/dL, P = .001). At the 3-year follow-up, new-onset AF was noted in 21 of the 188 living patients in the SR group. Cox proportional hazards analysis revealed ΔLDLc and ΔTC as independent risk factors for new-onset AF (hazard ratio, 1.018 and 1.013, respectively, per standard deviation increment), with higher incidence of new-onset AF for ΔTC > 9.65 mg/dL (P = .02) and for ΔLDLc > 9.73 mg/dL (P = .005).In CHF, pronounced decrease in LDLc and TC is associated with new-onset AF.
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http://dx.doi.org/10.1097/MD.0000000000012485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181553PMC
September 2018

O-Linked β-N-Acetylglucosamine Modification of A20 Enhances the Inhibition of NF-κB (Nuclear Factor-κB) Activation and Elicits Vascular Protection After Acute Endoluminal Arterial Injury.

Arterioscler Thromb Vasc Biol 2018 06 5;38(6):1309-1320. Epub 2018 Apr 5.

From the Department of Cardiology, the Affiliated Hospital of Yangzhou University (D.Y., L.X., O.X., R.L., M.C., H.S., H.Z., F.Z., D.Y., Z.Z., K.G.)

Objective: Recently, we have demonstrated that acute glucosamine-induced augmentation of protein O-linked β-N-acetylglucosamine (O-GlcNAc) levels inhibits inflammation in isolated vascular smooth muscle cells and neointimal formation in a rat model of carotid injury by interfering with NF-κB (nuclear factor-κB) signaling. However, the specific molecular target for O-GlcNAcylation that is responsible for glucosamine-induced vascular protection remains unclear. In this study, we test the hypothesis that increased A20 (also known as TNFAIP3 [tumor necrosis factor α-induced protein 3]) O-GlcNAcylation is required for glucosamine-mediated inhibition of inflammation and vascular protection.

Approach And Results: In cultured rat vascular smooth muscle cells, both glucosamine and the selective O-linked N-acetylglucosaminidase inhibitor thiamet G significantly increased A20 O-GlcNAcylation. Thiamet G treatment did not increase A20 protein expression but did significantly enhance binding to TAX1BP1 (Tax1-binding protein 1), a key regulatory protein for A20 activity. Adenovirus-mediated A20 overexpression further enhanced the effects of thiamet G on prevention of TNF-α (tumor necrosis factor-α)-induced IκB (inhibitor of κB) degradation, p65 phosphorylation, and increases in DNA-binding activity. A20 overexpression enhanced the inhibitory effects of thiamet G on TNF-α-induced proinflammatory cytokine expression and vascular smooth muscle cell migration and proliferation, whereas silencing endogenous A20 by transfection of specific A20 shRNA significantly attenuated these inhibitory effects. In balloon-injured rat carotid arteries, glucosamine treatment markedly inhibited neointimal formation and p65 activation compared with vehicle treatment. Adenoviral delivery of A20 shRNA to the injured arteries dramatically reduced balloon injury-induced A20 expression and inflammatory response compared with scramble shRNA and completely abolished the vascular protection of glucosamine.

Conclusions: These results suggest that O-GlcNAcylation of A20 plays a key role in the negative regulation of NF-κB signaling cascades in TNF-α-treated vascular smooth muscle cells in culture and in acutely injured arteries, thus protecting against inflammation-induced vascular injury.
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http://dx.doi.org/10.1161/ATVBAHA.117.310468DOI Listing
June 2018

Intraflagellar transporter protein 140 (IFT140), a component of IFT-A complex, is essential for male fertility and spermiogenesis in mice.

Cytoskeleton (Hoboken) 2018 02 8;75(2):70-84. Epub 2018 Jan 8.

Department of Obstetrics & Gynecology, Virginia Commonwealth University, Richmond, Virginia 23298.

Intraflagellar transport (IFT) is a conserved mechanism essential for the assembly and maintenance of most eukaryotic cilia and flagella. However, little is known about its role in sperm flagella formation and male fertility. IFT140 is a component of IFT-A complex. In mouse, it is highly expressed in the testis. Ift140 gene was inactivated specifically in mouse spermatocytes/spermatids. The mutant mice did not show any gross abnormalities, but all were infertile and associated with significantly reduced sperm number and motility. Multiple sperm morphological abnormalities were discovered, including amorphous heads, short/bent flagella and swollen tail tips, as well as vesicles along the flagella due to spermiogenesis defects. The epididymides contained round bodies of cytoplasm derived from the sloughing of the cytoplasmic lobes and residual bodies. Knockout of Ift140 did not significantly affect testicular expression levels of selective IFT components but localization of IFT27 and IFT88, two components of IFT-B complex, was changed. Our findings demonstrate that IFT140 is a key regulator for male fertility and normal spermiogenesis in mice. It not only plays a role in sperm flagella assembling, but is also involved in critical assembly of proteins that interface between the germ cell plasma and the Sertoli cell.
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http://dx.doi.org/10.1002/cm.21427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809318PMC
February 2018

Intraflagellar transporter protein (IFT27), an IFT25 binding partner, is essential for male fertility and spermiogenesis in mice.

Dev Biol 2017 12 28;432(1):125-139. Epub 2017 Sep 28.

Department of Obstetrics&Gynecology, Virginia Commonwealth University, Richmond, VA, 23298, USA. Electronic address:

Intraflagellar transport (IFT) is an evolutionarily conserved mechanism essential for the assembly and maintenance of most eukaryotic cilia and flagella. In mice, mutations in IFT proteins have been shown to cause several ciliopathies including retinal degeneration, polycystic kidney disease, and hearing loss. However, little is known about its role in the formation of the sperm tail, which has the longest flagella of mammalian cells. IFT27 is a component of IFT-B complex and binds to IFT25 directly. In mice, IFT27 is highly expressed in the testis. To investigate the role of IFT27 in male germ cells, the floxed Ift27 mice were bred with Stra8-iCre mice so that the Ift27 gene was disrupted in spermatocytes/spermatids. The Ift27: Stra8-iCre mutant mice did not show any gross abnormalities, and all of the mutant mice survived to adulthood. There was no difference between testis weight/body weight between controls and mutant mice. All adult homozygous mutant males examined were completely infertile. Histological examination of the testes revealed abnormally developed germ cells during the spermiogenesis phase. The epididymides contained round bodies of cytoplasm. Sperm number was significantly reduced compared to the controls and only about 2% of them remained significantly reduced motility. Examination of epididymal sperm by light microscopy and SEM revealed multiple morphological abnormalities including round heads, short and bent tails, abnormal thickness of sperm tails in some areas, and swollen tail tips in some sperm. TEM examination of epididymal sperm showed that most sperm lost the "9+2″ axoneme structure, and the mitochondria sheath, fibrous sheath, and outer dense fibers were also disorganized. Some sperm flagella also lost cell membrane. Levels of IFT25 and IFT81 were significantly reduced in the testis of the conditional Ift27 knockout mice, and levels of IFT20, IFT74, and IFT140 were not changed. Sperm lipid rafts, which were disrupted in the conditional Ift25 knockout mice, appeared to be normal in the conditional Ift27 knockout mice. Our findings suggest that like IFT25, IFT27, even though not required for ciliogenesis in somatic cells, is essential for sperm flagella formation, sperm function, and male fertility in mice. IFT25 and IFT27 control sperm formation/function through many common mechanisms, but IFT25 has additional roles beyond IFT27.
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http://dx.doi.org/10.1016/j.ydbio.2017.09.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694392PMC
December 2017

IFT25, an intraflagellar transporter protein dispensable for ciliogenesis in somatic cells, is essential for sperm flagella formation.

Biol Reprod 2017 May;96(5):993-1006

School of Public Health and Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, Wuhan, Hubei, China.

Intraflagellar transport (IFT) is a conserved mechanism essential for the assembly and maintenance of most eukaryotic cilia and flagella. However, IFT25, a component of the IFT complex, is not required for the formation of cilia in somatic tissues. In mice, the gene is highly expressed in the testis, and its expression is upregulated during the final phase when sperm flagella are formed. To investigate the role of IFT25 in sperm flagella formation, the gene was specifically disrupted in male germ cells. All homozygous knockout mice survived to adulthood and did not show any gross abnormalities. However, all homozygous knockout males were completely infertile. Sperm numbers were reduced and these sperm were completely immotile. Multiple morphological abnormalities were observed in sperm, including round heads, short and bent tails, with some tails showing branched flagella and others with frequent abnormal thicknesses, as well as swollen tips of the tail. Transmission electron microscopy revealed that flagellar accessory structures, including the fibrous sheath and outer dense fibers, were disorganized, and most sperm had also lost the "9+2" microtubule structure. In the testis, IFT25 forms a complex with other IFT proteins. In Ift25 knockout testes, IFT27, an IFT25 binding partner, was missing, and IFT20 and IFT81 levels were also reduced. Our findings suggest that IFT25, although not necessary for the formation of cilia in somatic cells, is indispensable for sperm flagellum formation and male fertility in mice.
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http://dx.doi.org/10.1093/biolre/iox029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355109PMC
May 2017

Triptolide attenuates pressure overload-induced myocardial remodeling in mice via the inhibition of NLRP3 inflammasome expression.

Biochem Biophys Res Commun 2017 03 12;485(1):69-75. Epub 2017 Feb 12.

Department of Cardiology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225012, China. Electronic address:

Triptolide is the predominant active component of the Chinese herb Tripterygium wilfordii Hook F (TwHF) that has been widely used to treat several chronic inflammatory diseases due to its immunosuppressive, anti-inflammatory, and anti-proliferative properties. In the present study, we elucidated the cardioprotective effects of triptolide against cardiac dysfunction and myocardial remodeling in chronic pressure-overloaded hearts. Furthermore, the potential mechanisms of triptolide were investigated. For this purpose, C57/BL6 mice were anesthetized and subjected to transverse aortic constriction (TAC) or sham operation. Six weeks after the operation, all mice were randomly divided into 4 groups: sham-operated with vehicle group, TAC with vehicle group, and TAC with triptolide (20 or 100 μg/kg/day intraperitoneal injection) groups. Our data showed that the levels of NLRP3 inflammasome were significantly increased in the TAC group and were associated with increased inflammatory mediators and profibrotic factor production, resulting in myocardial fibrosis, cardiomyocyte hypertrophy, and impaired cardiac function. Triptolide treatment attenuated TAC-induced myocardial remodeling, improved cardiac diastolic and systolic function, inhibited the NLRP3 inflammasome and downstream inflammatory mediators (IL-1β, IL-18, MCP-1, VCAM-1), activated the profibrotic TGF-β1 pathway, and suppressed macrophage infiltration in a dose-dependent manner. Our study demonstrated that the protective effect of triptolide against pressure overload in the heart may act by inhibiting the NLRP3 inflammasome-induced inflammatory response and activating the profibrotic pathway.
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http://dx.doi.org/10.1016/j.bbrc.2017.02.021DOI Listing
March 2017

[Isolation, purification and primary culture of adult mouse cardiac fibroblasts].

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2017 Jan;33(1):67-71

Department of Vasculocardiology, Second Clinical Medical College, Yangzhou University, Yangzhou 225012, China.

Objective To establish a method for primary culture of adult mouse cardiac fibroblasts. Methods Myocardial tissues from adult mice were digested with 1 g/L trypsin and 0.8 g/L collagenase IV by oscillating water bath for a short time repeatedly. Cardiac fibroblasts and myocardial cells were isolated with differential adhesion method. Immunofluorescence staining was used to assess the purity of cardiac fibroblasts. The cell morphology was observed under an inverted phase contrast microscope. The proliferation of cardiac fibroblasts was analyzed by growth curve and CCK-8 assay. The Smad2/3 phosphorylation induced by TGF-β1 was detected by Western blotting. Results After 90 minutes of differential adhesion, adherent fibroblasts formed spherical cell mass and after 3 days, cells were spindle-shaped and proliferated rapidly. Cells were confluent after 5 days and the growth curve presented nearly "S" shape. The positive expression rate of vimentin was 95%. CCK-8 assay showed that the optimal cell proliferating activity was found from day 3 to day 5. The level of phosphorylated Smad2/3 obviously increased at the second passage induced by TGF-β1. Conclusion This method is economical and stable to isolate cardiac fibroblasts with high activity and high purity from adult mice.
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January 2017

Smad3-mSin3A-HDAC1 Complex is Required for TGF-β1-Induced Transcriptional Inhibition of PPARγ in Mouse Cardiac Fibroblasts.

Cell Physiol Biochem 2016 7;40(5):908-920. Epub 2016 Dec 7.

Department of Cardiology, the Affiliated Hospital of Yangzhou University, Yangzhou, China.

Background: We have recently demonstrated that activated transforming growth factor-β (TGF-β) signaling suppresses myocardial peroxisome proliferator-activated receptor γ (PPARγ) expression in the pressure overloaded heart. In this study, we aim to further define the molecular mechanisms that underlie TGF-β-induced PPARγ transcriptional inhibition.

Methods: Adult mouse cardiac fibroblasts were isolated and cultured. PPARγ promoter activity was measured by the dual-Luciferase reporter assay. Interactions between transcription factors and the target gene were identified.

Results: In cultured cardiac fibroblasts transfected with a plasmid containing a human PPARγ promoter, co-transfection of Smad3 and Smad4, but not Smad2, plasmids significantly enhanced TGF-β1-induced inhibition of PPARγ promoter activity. Promoter deletion analysis and site-directed mutagenesis assays defined two Smad binding elements on the promoter of the PPARγ gene. Utilizing chromatin immunoprecipitation analysis and DNA-affinity precipitation methods, we demonstrated that the transcriptional regulatory complex consisting of Smad3, mSin3A and HDAC1 bound to the promoter of the PPARγ gene in cardiac fibroblasts in response to TGF-β1 stimulation. Either silencing endogenous mSin3A expression by Lentivirus-mediated transduction of mSin3A shRNA or pretreatment with the specific HDAC1 inhibitor MS-275 effectively attenuated TGF-β-induced transcriptional suppression of PPARγ.

Conclusion: These results suggest that TGF-β1-induced inhibition of PPARγ transcription depends on formation of a functional transcriptional regulatory complex that includes Smad3, mSin3A and HDAC1 at the PPARγ promoter.
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http://dx.doi.org/10.1159/000453149DOI Listing
February 2017

Intraflagellar transport protein IFT20 is essential for male fertility and spermiogenesis in mice.

Mol Biol Cell 2016 Sep 28. Epub 2016 Sep 28.

Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA, 23298

Intraflagellar transport (IFT) is a conserved mechanism thought to be essential for the assembly and maintenance of cilia and flagella. However, little is known about its role in mammalian sperm flagella formation. To fill this gap, we disrupted the Ift20 gene in male germ cells. Homozygous mutant mice were infertile with significantly reduced sperm counts and motility. In addition, abnormally shaped elongating spermatid heads and bulbous round spermatids were found in the lumen of the seminiferous tubules. Electron microscopy revealed increased cytoplasmic vesicles, fiber-like structures, abnormal accumulation of mitochondria and a decrease in mature lysosomes. The few developed sperm had disrupted axonemes and some retained cytoplasmic lobe components on the flagella. ODF2 and SPAG16L, two sperm flagella proteins failed to be incorporated into sperm tails of the mutant mice, and in the germ cells, both were assembled into complexes with lighter density in the absence of IFT20. Disrupting IFT20 did not significantly change expression levels of IFT88, a component of IFT-B complex, and IFT140, a component of IFT-A complex. Even though the expression level of an autophagy core protein that associates with IFT20, ATG16, was reduced in the testis of the Ift20 mutant mice, expression levels of other major autophagy markers, including LC3 and ubiquitin were not changed. Our studies suggest that IFT20 is essential for male fertility and spermiogenesis in mice, and its major function is to transport cargo proteins for sperm flagella formation. It also appears to be involved in removing excess cytoplasmic components.
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http://dx.doi.org/10.1091/mbc.E16-05-0318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5170554PMC
September 2016

Impaired immunological synapse in sperm associated antigen 6 (SPAG6) deficient mice.

Sci Rep 2016 05 12;6:25840. Epub 2016 May 12.

Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA.

Sperm associated antigen 6 (SPAG6), a component of the central apparatus of the "9 + 2" axoneme, plays a central role in ciliary and flagellar motility; but, its contribution to adaptive immunity and immune system development is completely unknown. While immune cells lack a cilium, the immunological synapse is a surrogate cilium as it utilizes the same machinery as ciliogenesis including the nucleation of microtubules at the centrosome. This prompted our hypothesis that SPAG6 critically regulates the formation and function of immunological synapses. Using bone marrow reconstitution studies of adult WT mice, we demonstrate that SPAG6 is expressed in primary and secondary lymphoid tissues, is associated with the centrosome in lymphocytes, and its deficiency results in synapse disruption due to loss of centrosome polarization and actin clearance at the synaptic cleft. Improper synapse formation in Spag6KO mice was associated with defective CTL functions and impaired humoral immunity as indicated by reduced germinal centers reactions, follicular CD4 T cells, and production of class-switched antibody, together with expansion of B1 B cells. This novel report demonstrates the requirement of SPAG6 for optimal synapse formation and function, its direct role in immune cell function, and provides a novel mechanism for infertility disorders related to SPAG6.
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http://dx.doi.org/10.1038/srep25840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864328PMC
May 2016

Protective effects of drag-reducing polymers in a rat model of monocrotaline-induced pulmonary hypertension.

Biorheology 2016 01;53(1):13-22

Department of Cardiovascular Diseases, The Second Clinical Medical College, Yangzhou University, Yangzhou, China.

Objectives: Drag-reducing polymers (DRPs) are blood-soluble macromolecules which may increase blood flow and reduce vascular resistance. The purpose of the present study was to observe the effect of DRPs on monocrotaline-induced pulmonary hypertension (PH) in the rat model.

Methods: A total of 64 male Wistar rats were randomly divided into four groups: Group I (pulmonary hypertension model + DRP treatment); Group II (pulmonary hypertension model + saline treatment); Group III (control + DRP treatment); Group IV (control + saline treatment). After five weeks, comparisons were made of the following indices: survival rate, body weight, blood pressure, right ventricular systolic pressure, right ventricular hypertrophy, wall thickness of pulmonary arteries, the internal diameter of small pulmonary arteries, plasma IL-1β and IL-6.

Results: The survival rate after 5 weeks varied significantly across all groups (P=0.013), but the survival rates of Groups I and II were not statistically significantly different. Administration of DRP (intravenous injection twice weekly) attenuated the PH-induced increase in right ventricular systolic pressure and suppressed the increases in right ventricular (RV) weight and the ratio of right ventricular weight to left ventricle plus septum weight (RV/LV + S). DRP treatment also significantly decreased the wall thickness of pulmonary arteries, augmented the internal diameter of small pulmonary arteries, and suppressed increases in the plasma levels of IL-1β and IL-6.

Conclusions: DRP treatment with intravenous injection effectively inhibited the development of monocrotaline-induced pulmonary hypertension in the rat model. DRPs may have potential application for the treatment of pulmonary hypertension.
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http://dx.doi.org/10.3233/BIR-15062DOI Listing
January 2016

Effect of rosuvastatin dose-loading on serum sLox-1, hs-CRP, and postoperative prognosis in diabetic patients with acute coronary syndromes undergoing selected percutaneous coronary intervention (PCI).

Int J Clin Exp Med 2015 15;8(11):21565-71. Epub 2015 Nov 15.

Institute of Cardiovascular for Southeast University, Department of Cardiology, Zhongda Hospital of Southeast University Medical School Nanjing 210000, China.

Objective: To investigate the effect of rosuvastatin dose-loading on serum levels of lectin-like oxidized low-density lipoprotein receptor-1 (Lox-1) and high-sensitivity c-reactive protein (hs-CRP) and postoperative prognosis in patients with diabetes and non-ST segment elevation acute coronary syndromes (NSTEACS) undergoing selected percutaneous coronary intervention (PCI).

Methods: A total of 72 patients with diabetes and NSTEACS were randomized to either the group treated with 20 mg rosuvastatin 12 hours prior to PCI with a second dose administered just before PCI (n = 33), or a control group treated with standard method according guideline (n = 39). Serum levels of sLox-1, hs-CRP, CK-MB, and cTnI were measured prior to PCI, and at 24 hours and 30 days after PCI. The 30-day incidence of major adverse cardiac events (MACE) was recorded in both groups.

Results: Compared to pre-PCI, serum levels of sLox-1 and hs-CRP of the two groups were increased at 24 hours after PCI (P < 0.05); the levels of CK-MB and cTnI were also improved (P < 0.01); however, the ascended values of sLox-1, hs-CRP, CK-MB, and cTnI were significantly lower in the loading-dose rosuvastatin-treated group than in the control-treated group. Serum levels of sLox-1 and hs-CRP were higher in the loading-dose rosuvastatin-treated group than in the control-treated group at 30 days after PCI (P < 0.05); compared to pre-PCI, the levels of TC and LDL-C were not changed at 24 hours after PCI (P > 0.05) until 30 days after PCI (P < 0.05), but there were no difference between the two groups. The levels of ALT and Scr had no significant difference between the two groups before and after PCI; the 30-day incidence of MACE occurred in 6.06% of patients in the loading-dose rosuvastatin-treated group and in 23.08% of patients in the control-treated group (P < 0.05).

Conclusion: The therapy of dose-loading rosuvastatin for patients with diabetes and non-ST segment elevation acute coronary syndromes undergoing selected percutaneous coronary intervention can attenuate the increase of serum levels of sLox-1, reduce myocardial injury and inflammatory reaction caused by PCI, and also reduce the occurrence of MACE 30 days after PCI.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4723951PMC
February 2016

Lipoxin A4 exerts protective effects against experimental acute liver failure by inhibiting the NF-κB pathway.

Int J Mol Med 2016 Mar 5;37(3):773-80. Epub 2016 Feb 5.

Department of Infection, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.

Although rare, acute liver failure (ALF) is associated with high levels of mortality, warranting the development of novel therapies. Nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) play roles in ALF. Lipoxin A4 (LXA4) has been shown to alleviate inflammation in non-hepatic tissues. In the present study, we explored whether LXA4 exerted hepatoprotective effects in a rat model of ALF. A rat model of ALF was generated by intraperitoneal injections of D-galactosamine (300 mg/kg) and lipopolysaccharide (50 µg/kg). Animals were randomly assigned to: control group (no ALF); model group (ALF); and the groups treated with a low dose (0.5 µg/kg), medium dose (1 µg/kg), and high dose (2 µg/kg) of LXA4 (all with ALF); and pyrrolidine dithiocarbamate (PDTC)-treated group (ALF and 100 mg/kg PDTC, an inhibitor of NF-κB). Liver histology was measured using H&E staining, serum levels by ELISA, and liver mRNA expression was measured by RT-PCR for the detection of the pro‑inflammatory cytokines TNF-α and IL-6. Liver cell apoptosis (as measured using the TUNEL method and examining caspase-3 activity), and Kupffer cell NF-κB activity [using an electrophoretic mobility shift assay (EMSA)] were examined. Serum levels of transaminases, TNF-α and interleukin-6 (IL-6) were substantially higher in the model group compared to controls. In the model group, significant increases in TNF-α and IL-6 mRNA expression, TUNEL‑positive cells, and caspase-3 activity in the liver tissue were noted. LXA4 improved liver pathology and significantly decreased the indicators of inflammatory response and apoptosis in a dose-dependent manner. High-dose LXA4 provided better protection than PDTC. LXA4 administration significantly decreased NF-κB expression in hepatocytes and Kupffer cells. These results indicated that LXA4 inhibited NF-κB activation, reduced the secretion of pro-inflammatory cytokines, and inhibited apoptosis of liver cells, thereby exerting protective effects against ALF.
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http://dx.doi.org/10.3892/ijmm.2016.2483DOI Listing
March 2016

Efficacy and Safety of Loading-Dose Rosuvastatin Therapy in Elderly Patients with Acute Coronary Syndromes Undergoing Elective Percutaneous Coronary Intervention.

Clin Drug Investig 2015 Dec;35(12):777-84

Department of Cardiology, Institute of Cardiovascular Disease, Zhongda Hospital of Southeast University Medical School, Southeast University, Nanjing, 210000, China.

Objectives: The aim of this work was to investigate the efficacy and safety of loading-dose rosuvastatin therapy in elderly patients with non-ST-segment elevation acute coronary syndromes (NSTEACS) undergoing elective percutaneous coronary intervention (PCI).

Methods: A total of 126 patients (≥70 years old) with NSTEACS were randomly divided into two groups: (1) loading-dose rosuvastatin-treated group, treated with rosuvastatin 20 mg 12 h prior to PCI, with a second dose administered just before PCI (n = 62), and (2) control-treated group, treated with the standard method according to ACC/AHA guidelines in UAP/NSTEMI 2007 (n = 64). All patients were required to take rosuvastatin 10 mg once a day starting 24 h after the surgery irrespective of the initial randomization assignment. The serum soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLox-1), high-sensitivity C-reactive protein (hs-CRP), creatinine kinase (CK)-MB, cardiac troponin I (cTnI), and brain natriuretic peptide (BNP) levels were measured prior to PCI and at 24 h and 30 days after PCI in both groups. The left ventricular ejection fraction (LVEF) levels were recorded prior to PCI and 30 days after PCI in both groups.

Results: Compared to pre-PCI, the serum sLox-1, hs-CRP, CK-MB, and cTnI levels were increased at 24 h after PCI (all p < 0.05) in both groups. However, the increased sLox-1, hs-CRP, CK-MB, and cTnI values were significantly lower in the loading-dose rosuvastatin-treated group than in the control-treated group (p < 0.05). In addition the serum sLox-1 and hs-CRP levels were lower in the loading-dose rosuvastatin-treated group than in the control-treated group at 30 days after PCI. However, the decreased values of sLox-1and hs-CRP from 24 h after PCI to 30 days after PCI did not show any significant difference between the two groups. No significant difference was found in the serum ALT and Scr levels between the two groups before and after PCI. Compared to the control-treated group, the serum BNP level decreased (p < 0.05) and LVEF (p < 0.05) increased in the loading-dose rosuvastatin-treated group at 30 days after PCI.

Conclusion: The loading-dose rosuvastatin therapy in elderly patients with non-ST-segment elevation acute coronary syndromes undergoing elective PCI can attenuate the increase in serum hs-CRP, sLox-1, CK-MB, and cTnI levels, reduce myocardial injury and inflammatory reaction caused by PCI, and improve the LVEF level at 30 days after PCI, ensuring an effective and safe therapy.
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http://dx.doi.org/10.1007/s40261-015-0335-1DOI Listing
December 2015

RC/BTB2 is essential for formation of primary cilia in mammalian cells.

Cytoskeleton (Hoboken) 2015 Apr 29;72(4):171-81. Epub 2015 Apr 29.

School of Public Health, Wuhan University of Science and Technology, Wuhan, Hubei, China.

RC/BTB2 is a binding partner of sperm associated antigen 16S (SPAG16S), which is a regulator of spermiogenesis in mice, a process during which sperm flagella are formed. The expression of Rc/btb2 is also regulated by multicilin, a protein that controls ciliogenesis. Given that mouse Rc/btb2 mRNA is not only expressed in tissues bearing motile cilia, but also in tissues without motile cilia, we investigated whether RC/BTB2 plays a role in the general process of ciliogenesis by studying two cell lines that have primary cilia, NIH3T3, and IMCD3. We discovered that the subcellular localization of RC/BTB2 in the NIH3T3 and IMCD3 cells encompasses the pathway for ciliogenesis. RC/BTB2 was found in the Golgi bodies and centrosomes, two key structures essential for normal ciliogenesis. Knockdown of Rc/btb2 gene expression in these cell lines disrupted ciliogenesis. The percentage of cells with primary cilia was significantly reduced in stable cell lines transduced with specific Rc/btb2 shRNA viruses as compared to the control cells. When cilia were formed in the knockdown cells, they were significantly shorter than those in the control cells. Knockdown of Rc/btb2 expression did not affect cell proliferation and the cell cycle. Exogenous expression of RC/BTB2 in these stable knockdown cells restored ciliogenesis. These findings suggest that RC/BTB2 is a necessary component of the process of formation of primary cilia in somatic cells, perhaps through the transportation of cargos from Golgi bodies to centrosomes for cilia assembling.
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http://dx.doi.org/10.1002/cm.21214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758837PMC
April 2015

A MEIG1/PACRG complex in the manchette is essential for building the sperm flagella.

Development 2015 Mar;142(5):921-30

Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA 23298, USA School of Public Health, Wuhan University of Science and Technology, Wuhan, Hubei 430081, China Department of Biochemistry & Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA

A key event in the process of spermiogenesis is the formation of the flagella, which enables sperm to reach eggs for fertilization. Yeast two-hybrid studies revealed that meiosis-expressed gene 1 (MEIG1) and Parkin co-regulated gene (PACRG) interact, and that sperm-associated antigen 16, which encodes an axoneme central apparatus protein, is also a binding partner of MEIG1. In spermatocytes of wild-type mice, MEIG1 is expressed in the whole germ cell bodies, but the protein migrates to the manchette, a unique structure at the base of elongating spermatid that directs formation of the flagella. In the elongating spermatids of wild-type mice, PACRG colocalizes with α-tubulin, a marker for the manchette, whereas this localization was not changed in the few remaining elongating spermatids of Meig1-deficient mice. In addition, MEIG1 no longer localizes to the manchette in the remaining elongating spermatids of Pacrg-deficient mice, indicating that PACRG recruits MEIG1 to the manchette. PACRG is not stable in mammalian cells, but can be stabilized by MEIG1 or by inhibition of proteasome function. SPAG16L is present in the spermatocyte cytoplasm of wild-type mice, and in the manchette of elongating spermatids, but in the Meig1 or Pacrg-deficient mice, SPAG16L no longer localizes to the manchette. By contrast, MEIG1 and PACRG are still present in the manchette of Spag16L-deficient mice, indicating that SPAG16L is a downstream partner of these two proteins. Together, our studies demonstrate that MEIG1/PACRG forms a complex in the manchette and that this complex is necessary to transport cargos, such as SPAG16L, to build the sperm flagella.
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http://dx.doi.org/10.1242/dev.119834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352978PMC
March 2015

Protective effects of drag-reducing polymers on ischemic reperfusion injury of isolated rat heart.

Clin Hemorheol Microcirc 2016 ;62(1):1-11

Drag-reducing polymers (DRPs) are blood-soluble macromolecules that can increase blood flow and reduce vascular resistance. The purpose of the present study was to observe the effect of DRPs on ischemic reperfusion (I/R) injury of isolated rat hearts. Experiments were performed on isolated rat hearts subjected to 30 min of ischemia followed by 90 min of reperfusion in Langendorff preparations. Adult Wistar rats were divided into the following five groups: control group, I/R group, group III (I/R and 2×10(-7)  g/ml PEO reperfusion), group IV (I/R and 1×10(-6)  g/ml PEO reperfusion), and group V (I/R and 5×10(-6)  g/ml PEO reperfusion). Left ventricular end-diastolic pressure (LVEDP), left ventricular systolic pressure (LVSP), maximum rate of ventricular pressure increase and decrease ( ± dp/dtmax), heart rate (HR) and coronary flow were measured. Lactate dehydrogenase (LDH) and creatine kinase (CK) activity and coronary flow, myocardial infarction size and cardiomyocytes apoptosis were also assayed. Our results showed that PEO decreased LVEDP and increased LVSP, ± dP/dtmax in group IV and group V compared with the I/R group (all P <  0.05). The coronary flow significantly increased and the activities of LDH and CK in the coronary flow significantly decreased in group IV and group V compared with those in the I/R group (all P <  0.05). Cell apoptosis and myocardial infarction size were reduced in group IV and group V compared with the I/R group (all P <  0.05). Collectively, these results suggested that DRPs had a protective effect on cardiac I/R injury of isolated rat hearts and it may offer a new potential approach for the treatment of acute ischemic heart diseases.
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http://dx.doi.org/10.3233/CH-151925DOI Listing
November 2016

Sperm-associated antigen 6 (SPAG6) deficiency and defects in ciliogenesis and cilia function: polarity, density, and beat.

PLoS One 2014 21;9(10):e107271. Epub 2014 Oct 21.

Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia, United States of America; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia, United States of America.

SPAG6, an axoneme central apparatus protein, is essential for function of ependymal cell cilia and sperm flagella. A significant number of Spag6-deficient mice die with hydrocephalus, and surviving males are sterile because of sperm motility defects. In further exploring the ciliary dysfunction in Spag6-null mice, we discovered that cilia beat frequency was significantly reduced in tracheal epithelial cells, and that the beat was not synchronized. There was also a significant reduction in cilia density in both brain ependymal and trachea epithelial cells, and cilia arrays were disorganized. The orientation of basal feet, which determines the direction of axoneme orientation, was apparently random in Spag6-deficient mice, and there were reduced numbers of basal feet, consistent with reduced cilia density. The polarized epithelial cell morphology and distribution of intracellular mucin, α-tubulin, and the planar cell polarity protein, Vangl2, were lost in Spag6-deficient tracheal epithelial cells. Polarized epithelial cell morphology and polarized distribution of α-tubulin in tracheal epithelial cells was observed in one-week old wild-type mice, but not in the Spag6-deficient mice of the same age. Thus, the cilia and polarity defects appear prior to 7 days post-partum. These findings suggest that SPAG6 not only regulates cilia/flagellar motility, but that in its absence, ciliogenesis, axoneme orientation, and tracheal epithelial cell polarity are altered.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0107271PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4204823PMC
June 2015

Triptolide protects rat heart against pressure overload-induced cardiac fibrosis.

Int J Cardiol 2013 Oct 27;168(3):2498-505. Epub 2013 Mar 27.

Department of Cardiology, the Second Clinic Medical College, Yangzhou University, Yangzhou, 225001, China; Department of Clinical Medicine, Yangzhou University Medical College, Yangzhou, 225001, China.

Background: Emerging evidence underlines the role of inflammation activation in the process of cardiac fibrosis. Triptolide has potent anti-inflammatory and anti-proliferative properties, and extensively used in the treatment of chronic inflammatory disorders. In the current study, we test the hypothesis that triptolide treatment facilitates to attenuate chronic pressure overload-induced cardiac fibrosis in a model of rat.

Methods: Adult male Sprague-Dawley rats were subjected to a suprarenal abdominal aorta constriction (AC) or sham (as control) to induce sustained pressure overload. Eight weeks later, rats were randomly assigned to receive triptolide (9 μg/kg.d, i.p) or vehicle (0.1% dimethyl sulfoxide, 0.2 ml/d, i.p) treatment for an additional 8 weeks.

Results: AC caused significant pathological hypertrophy, cardiac fibrosis and reduced cardiac diastolic function. Triptolide treatment markedly inhibited AC-induced increases in myocardial collagen volume fraction, collagen type I/III deposition, left ventricular end-diastolic pressure, expressions of pro-fibrogenic factors (transforming growth factor-β and angiotensin II) and pro-inflammatory cytokines (IL-1β and IL-6), NF-κB activation and inflammatory cell infiltration in left ventricles compared with vehicle, without affecting cardiac hypertrophy. However, triptolide had no effects on systemic blood pressure and circulating angiotensin II level.

Conclusions: Collectively, the findings suggested that triptolide treatment elicits favorable anti-fibrogenic effect in a blood pressure-independent manner, at least in part, through inhibiting myocardial pro-fibrogenic factor production and inflammatory activation in the pressure overloaded heart.
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http://dx.doi.org/10.1016/j.ijcard.2013.03.001DOI Listing
October 2013

Reverse apolipoprotein A-I mimetic peptide R-D4F inhibits neointimal formation following carotid artery ligation in mice.

Am J Pathol 2013 May 15;182(5):1932-9. Epub 2013 Mar 15.

Department of Cardiology, Second Clinic Medical College, Yangzhou University, Yangzhou, China.

The ApoA-I mimetic peptide D-4F has demonstrated potent atheroprotective actions in vivo and in vitro. We investigated the effect of R-D4F (ie, the D-4F peptide with reverse order of amino acids) on intimal hyperplasia after vascular injury in a mouse model of carotid artery ligation. Adult male C57BL/6J mice were pretreated intraperitoneally with vehicle, D-4F (1 mg/kg), or R-D4F (1 mg/kg or 5 mg/kg) daily for 3 days; the mice were then subjected to left carotid artery ligation. All treatments were continued for 28 days after surgery. Neither D-4F nor R-D4F treatment affected serum lipid levels. Morphometric analysis showed that the occluded vessels had significant neointimal formation, compared with the uninjured arteries in vehicle-treated mice. Like the D-4F treatment, R-D4F treatment significantly (P < 0.05) inhibited intimal hyperplasia (-42%), local neutrophil and macrophage infiltration, and mRNA expression of the proinflammatory mediator monocyte chemotactic protein 1 (-55%) and vascular cell adhesion protein 1 (-53%), compared with vehicle. Furthermore, the vasoprotective effect of high-dose R-D4F was significantly enhanced, compared with the low dose. In cultured mouse RAW 264.7 macrophages, pretreatment with R-D4F also effectively inhibited lipopolysaccharide-induced leukocyte integrin CD11b expression, a key molecule for leukocyte infiltration. Taken together, these results suggest that R-D4F has significant anti-inflammatory features and facilitates prevention of neointimal formation after vascular injury in mice.
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http://dx.doi.org/10.1016/j.ajpath.2013.01.040DOI Listing
May 2013