TRPC6 promotes daunorubicin-induced mitochondrial fission and cell death in rat cardiomyocytes with the involvement of ERK1/2-DRP1 activation.

Daunorubicin (DNR-) induced cardiotoxicity seriously restricts its clinical application. Transient receptor potential cation channel subfamily C member 6 (TRPC6) is involved in multiple cardiovascular physiological and pathophysiological processes. However, the role of TRPC6 anthracycline-induced cardiotoxicity (AIC) remains unclear. Mitochondrial fragmentation greatly promotes AIC. TRPC6-mediated ERK1/2 activation has been shown to favor mitochondrial fission in dentate granule cells. The aim of the present study was to elucidate the effects of TRPC6 on daunorubicin- induced cardiotoxicity and identify the mechanisms associated with mitochondrial dynamics. The sparkling results showed that TRPC6 was upregulated in models in vitro and in vivo. TRPC6 knockdown protected cardiomyocytes from DNR-induced cell apoptosis and death. DNR largely facilitated mitochondrial fission, boosted mitochondrial membrane potential collapse and damaged debilitated mitochondrial respiratory function in H9c2 cells，these effects were accompanied by TRPC6 upregulation. siTRPC6 effectively inhibited these mitochondrial adverse aspects showing a positive unexposed effect on mitochondrial morphology and function. Concomitantly, ERK1/2-DRP1 which is related to mitochondrial fission was significantly activated with amplified phosphorylated forms in DNR-treated H9c2 cells. siTRPC6 effectively suppressed ERK1/2-DPR1 over activation, hinting at a potential correlation between TRPC6 and ERK1/2-DRP1 by which mitochondrial dynamics are possibly modulated in AIC. TRPC6 knockdown also raised the Bcl-2/Bax ratio, which may help to block mitochondrial fragmentation-related functional impairment and apoptotic signaling. These findings suggested an essential role of TRPC6 in AIC by intensifying mitochondrial fission and cell death via ERK1/2-DPR1, which could be a potential therapeutic target for AIC.

Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15.

Hemangioblastoma (HB) is an abnormal intracranial buildup of blood vessels that exhibit a great potential for hemorrhage. Surgical options are limited, and few medications are available for treatment. We show here by immunohistochemical analysis that HB lesions display highly increased levels of VEGF expression and macrophage/microglia infiltration compared with those in normal brain tissues. In the meantime, TNF superfamily 15 (TNFSF15) (also known as vascular endothelial growth inhibitor), an antiangiogenic cytokine, is highly expressed in normal brain blood vessels but diminished in HB lesions. We set up a brain hemangioma model by using mouse bEnd.3 cells of a T antigen-transformed endothelial cell line that produce a large amount of VEGF. When implanted in mouse brains, these cells form lesions that closely resemble the pathologic characteristics of HB. Retroviral infection of bEnd.3 cells with TNFSF15 leads to inhibition of VEGF production and retardation of hemangioma formation. Similar results are obtained when wild-type bEnd.3 cells are implanted in the brains of transgenic mice overexpressing TNFSF15. Additionally, TNFSF15 treatment results in enhanced pericyte coverage of the blood vessels in the lesions together with reduced inflammatory cell infiltration and decreased hemorrhage. These findings indicate that the ability of TNFSF15 to counterbalance the abnormally highly angiogenic and inflammatory potential of the microenvironment of HB is of therapeutic value for the treatment of this disease.-Yang, G.-L., Han, Z., Xiong, J., Wang, S., Wei, H., Qin, T.-T., Xiao, H., Liu, Y., Xu, L.-X., Qi, J.-W., Zhang, Z.-S., Jiang, R., Zhang, J., Li, L.-Y. Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15.

Tumour necrosis factor superfamily member 15 (Tnfsf15) facilitates lymphangiogenesis via up-regulation of Vegfr3 gene expression in lymphatic endothelial cells.

Lymphangiogenesis is essential in embryonic development but is rare in adults. It occurs, however, in many disease conditions including cancers. Vascular endothelial growth factor-C/D (VEGF-C/D) and VEGF receptor-3 (Vegfr3) play a critical role in the regulation of lymphangiogenesis. We investigated how the VEGF-C/Vegfr3 signalling system is regulated by tumour necrosis factor superfamily member 15 (Tnfsf15), an endothelium-derived cytokine. We report here that Tnfsf15, which is known to induce apoptosis in vascular endothelial cells, can promote lymphatic endothelial cell (LEC) growth and migration, stimulate lymphangiogenesis, and facilitate lymphatic circulation. Treatment of mouse LECs with Tnfsf15 results in up-regulation of Vegfr3 expression; this can be inhibited by gene silencing of death domain-containing receptor-3 (DR3; Tnfrsf25), a cell surface receptor for Tnfsf15, with siRNA, or by blocking Tnfsf15-DR3 interaction with a Tnfsf15 neutralizing antibody, 4-3H. Additionally, Tnfsf15/DR3 signalling pathways in LECs include activation of NF-κB. Tnfsf15-overexpressing transgenic mice exhibit a marked enhancement of lymph drainage; this is confirmed by treatment of wild-type mice with intraperitoneal injection of recombinant Tnfsf15. Moreover, systemic treatment of pregnant Tnfsf15 transgenic mice with 4-3H leads to inhibition of embryonic lymphangiogenesis. Our data indicate that Tnfsf15, a cytokine produced largely by endothelial cells, facilitates lymphangiogenesis by up-regulating Vegfr3 gene expression in LECs, contributing to the maintenance of the homeostasis of the circulatory system. This finding also suggests that Tnfsf15 may be of potential value as a therapeutic tool for the treatment of lymphoedema.

TNFSF15 inhibits vasculogenesis by regulating relative levels of membrane-bound and soluble isoforms of VEGF receptor 1.

Mouse bone marrow-derived Lin(-)-Sca-1(+) endothelial progenitor cell (EPC) has pluripotent abilities such as supporting neovascularization. Vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1) (Flt1) recognizes various VEGF isoforms and is critically implicated in a wide range of physiological and pathological settings, including vasculogenesis. Mouse EPC expresses two isoforms of VEGFR1: mFlt1, which transmits ligand-induced signals; and sFlt1, which acts as a negative regulator by sequestering ligands of VEGF receptors. How the relative levels of mFlt1 and sFlt1 are regulated is not yet clear. We report here that tumor necrosis factor superfamily 15 (TNFSF15) (also known as VEGI or TL1A), an endothelial cell-secreted cytokine, simultaneously promotes mFlt1 degradation and up-regulates sFlt1 expression in EPC, giving rise to disruption of VEGF- or PlGF-induced activation of eNOS and MAPK p38 and effective inhibition of VEGF-driven, EPC-supported vasculogenesis in a murine Matrigel implant model. TNFSF15 treatment of EPC cultures facilitates Akt deactivation-dependent, ubiquitin-assisted degradation of mFlt1 and stimulates sFlt1 expression by activating the PKC, Src, and Erk1/2 signaling pathway. Additionally, TNFSF15 promotes alternative splicing of the Flt1 gene in favor of sFlt1 production by down-regulating nuclear protein Jumonji domain-containing protein 6 (Jmjd6), thus alleviating Jmjd6-inhibited sFlt1 expression. These findings indicate that TNFSF15 is a key component of a molecular mechanism that negatively modulates EPC-supported vasculogenesis through regulation of the relative levels of mFlt1 and sFlt1 in EPC.

N-acetylgalactosamine exposure of serum IgA1 was associated with glomerulosclerosis and tubular atrophy/interstitial fibrosis of IgA nephropathy patients.

AIM: Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis with various histological and clinical phenotypes. N-acetylgalactosamine (GalNAc) exposure plays a pivotal role in the pathogenesis of IgAN. The aim of the current study is to investigate whether GalNAc exposure of serum IgA1 was associated with clinical and pathological manifestation of IgAN. METHODS: Sera from 199 patients with biopsy proved IgAN were collected. Clinical and pathological manifestations were collected. Biotinylated Helix aspersa were used in ELISA to examine GalNAc exposure on IgA1 molecules. Patients were divided into two groups according to the GalNAc exposure rate less or more than 0.4. RESULTS: Age, gender, and serum creatinine were comparable between the two groups. Univariate analysis showed that significantly higher urinary protein excretion rate but less severe glomerular sclerosis and tubularinterstitial fibrosis were observed in the lower GalNAc exposure group. Multivariate regression analysis demonstrated that adjusted by age and gender, the GalNAc exposure rate more than 0.4 was a risk factor of glomerular sclerosis and tubularinterstitial fibrosis, OR*(95% CI) were 2.76 (1.19-6.37) and 2.49 (1.18-5.25), respectively. CONCLUSION: Immunoglobulin A nephropathy patients with lower proteinuria had higher GalNAc exposure rates. The GalNAc exposure rate more than 0.4 was a risk factor of severe chronic renal tissue change.

Therapeutic effects of ginsenosides on osteoporosis for novel drug applications.

Osteoporosis (OP) is a metabolic bone disease with a high incidence rate worldwide. Its main features are decreased bone mass, increased bone fragility and deterioration of bone microstructure. It is caused by an imbalance between bone formation and bone resorption. Ginsenoside is a safe and effective traditional Chinese medicine (TCM) usually extracted from ginseng plants, having various therapeutic effects, of which the effect against osteoporosis has been extensively studied. We searched a total of 44 relevant articles with using keywords including osteoporosis, ginsenosides, bone mesenchymal cells, osteoblasts, osteoclasts and bone remodeling, all of which investigated the cellular mechanisms of different types of ginsenosides affecting the activity of bone remodeling by mesenchymal stem cells, osteoblasts and osteoclasts to counteract osteoporosis. This review describes the different types of ginsenosides used to treat osteoporosis from different perspectives, providing a solid theoretical basis for future clinical applications.

Serum BAFF and APRIL might be associated with disease activity and kidney damage in patients with anti-glomerular basement membrane disease.

AIM: B cell activating factor belonging to the tumour necrosis factor family (BAFF) and a proliferation inducing ligand (APRIL) are two tumour necrosis factor (TNF)-like cytokines that were found to be elevated in many autoimmune diseases. Anti-glomerular basement membrane (GBM) disease is a typical severe autoimmune disease characterized by raised serum anti-GBM antibodies. In this study we aimed to detect the serum levels of BAFF and APRIL in patients with anti-GBM disease, and their clinical significance was further analyzed. METHODS: Forty-seven patients with anti-GBM disease were enrolled in this study. Forty-eight healthy individuals were used as normal controls. The levels of serum BAFF and APRIL were assessed using commercially available enzyme linked immunosorbent assay kits. The association between the levels of serum BAFF and APRIL, and the clinical and pathological parameters were further evaluated. RESULTS: The serum levels of BAFF and APRIL in patients with anti-GBM disease were significantly higher than that in normal controls (12.3 ± 14.1 ng/mL vs. 0.9 ± 0.3 ng/mL, P < 0.001; 19.1 ± 22.9 ng/mL vs. 1.6 ± 4.6 ng/mL, P < 0.001), respectively. The levels of serum APRIL were correlated with the titres of anti-GBM antibodies (r = 0.347, P = 0.041), and the levels of serum BAFF were associated with the percentage of glomeruli with crescents (r = 0.482, P = 0.015) in patients with anti-GBM disease. CONCLUSION: The levels of serum BAFF and APRIL were raised in patients with anti-GBM disease and might be associated with disease activity and kidney damage.

Effects of peripheral blood neutrophil/lymphocyte ratio levels and their changes on the prognosis of patients with early cervical cancer.

Although some studies have reported on the levels and clinical significance of peripheral blood neutrophil/lymphocyte ratio (NLR) in cervical cancer, the role of NLR levels and their changes preoperatively and postoperatively in early cervical cancer remain unclear. Our analyses explored the preoperative and postoperative NLR in 203 patients with stage I-IIA cervical cancer and evaluated the relationship between NLR changes, clinicopathological characteristics, and patient prognosis. The cut-off preoperative and postoperative NLR values were determined using receiver operating characteristic curve analysis. Preoperative NLR correlated with age, menopausal status, tumor size, and vascular infiltration, whereas postoperative NLR correlated with tumor differentiation. Patients with cervical cancer with a high preoperative NLR had significantly shorter overall survival (OS) and progression-free survival (PFS) than other patients, whereas PFS was significantly lower in the high postoperative NLR group. When comparing postoperative and preoperative NLR values, we observed a significantly higher rate of increase in postmenopausal patients and those without vascular infiltration than that among premenopausal patients and those with vascular infiltration. However, no clear difference in prognosis was observed between the groups with increased and decreased NLR. Therefore, a high peripheral blood NLR may predict a poor prognosis in patients with early cervical cancer. The effect of NLR changes on the prognosis of patients with cervical cancer requires further verification in multicenter studies.

SEPT2 crotonylation promotes metastasis and recurrence in hepatocellular carcinoma and is associated with poor survival.

BACKGROUND: Hepatocellular carcinoma (HCC) metastasis and recurrence lead to therapy failure, which are closely associated with the proteome. However, the role of post-translational modification (PTM) in HCC, especially for the recently discovered lysine crotonylation (Kcr), is elusive. RESULTS: We investigated the correlation between crotonylation and HCC in 100 tumor tissues and performed stable isotope labeling by amino acids and liquid chromatography tandem mass spectrometry in HCC cells, and we found that crotonylation was positively correlated with HCC metastasis, and higher crotonylation in HCC cells facilitated cell invasiveness. Through bioinformatic analysis, we found that the crotonylated protein SEPT2 was significantly hypercrotonylated in highly invasive cells, while the decrotonylated mutation of SEPT2-K74 impaired SEPT2 GTPase activity and inhibited HCC metastasis in vitro and in vivo. Mechanistically, SIRT2 decrotonylated SEPT2, and P85α was found to be the downstream effector of SEPT2. Moreover, we identified that SEPT2-K74cr was correlated with poor prognosis and recurrence in HCC patients, thus indicating its clinical potential as an independent prognostic factor. CONCLUSIONS: We revealed the role of nonhistone protein crotonylation in regulating HCC metastasis and invasion. Crotonylation facilitated cell invasion through the crotonylated SEPT2-K74-P85α-AKT pathway. High SEPT2-K74 crotonylation predicted poor prognosis and a high recurrence rate in HCC patients. Our study revealed a novel role of crotonylation in promoting HCC metastasis.

PD-1-mAb Plus Regimen in the First and Second Lines of Advanced and Unresectable Biliary Tract Carcinoma: A Real-World, Multicenter Retrospective Analysis.

Introduction: Advanced biliary tract carcinoma (BTC) has a poor prognosis and few treatment options. We compared the efficacy of the PD-1 monoclonal antibody (PD-1-mAb) combined regimens with the standard chemotherapy in the first-line and second-line treatment of advanced BTC. Methods: We retrospectively assessed the patients with advanced BTC, who received treatment at the First Affiliated Hospital of Sun Yat-Sen University and the Sun Yat-Sen University Cancer Center. The patients were treated with PD-1-mAb combined regimens or standard chemotherapy at the first line or treated with PD-1-mAb combined regimens or systematic therapy at the second line. Further subgroup analyses were assessed to identify superior regimens. Results: This study included 210 patients. The first-line PD-1-mAb combination group (n = 83) achieved longer median PFS (mPFS) (7.3 vs 5.3 months, p=0.001) and median OS (mOS) (15.6 vs 11.4 months, p=0.002) than the first-line standard chemotherapy group (n=76). Similarly, the second-line PD-1-mAb combination group (n=50) yielded longer mPFS (6.1 vs 2.6 months, p<0.001) and mOS (11.7 vs 7.2 months, p=0.008) than the second-line systematic therapy group (n=51). Subgroup analyses showed that the PD-1-mAb combined with TKI group achieved better mPFS than the chemotherapy group whether in the first-line (HR = 0.468, p=0.005) or the second-line setting (HR = 0.45, p=0.009), but did not achieve superiority in mOS (both p>0.05). Compared with the chemotherapy group, the PD-1-mAb combined with chemotherapy group achieved longer mOS (HR = 0.53, p=0.023) in the first-line setting and longer mPFS in the second-line setting (HR = 0.54, p=0.044). Conclusion: The PD-1-mAb combination therapy is superior to the standard chemotherapy in advanced or unresectable BTC, whether as a first-line or second-line treatment. Among the combination therapy, both the PD-1-mAb combined with TKI and combined with standard chemotherapy were promising options for advanced BTC patients.

The efficacy and safety of tacrolimus and entecavir combination therapy in the treatment of hepatitis B virus-associated glomerulonephritis: a multi-center, placebo controlled, and single-blind randomized trial.

BACKGROUND: The proteinuria remission in hepatitis B virus-associated glomerulonephritis (HBV-GN) patients with massive proteinuria treated with antiviral therapy was low. Tacrolimus (TAC) is effective in primary nephropathy and can inhibit HBV infection by inhibiting HBV binding to sodium taurocholate cotransporting polypeptide on liver cells. This study evaluated the efficacy and safety of TAC combined with ETV compared with entecavir (ETV) monotherapy in HBV-GN. METHODS: Patients diagnosed with HBV-GN were recruited for this prospective, randomized, controlled, multicenter, single-blinded study in China. Patients were given TAC and ETV therapy (the TAC+ETV group) or placebo and ETV therapy (the ETV group) for 26 weeks. The efficacy endpoints included proteinuria remission, including complete and partial remission (CR and PR), the change of 24-hour proteinuria (24 h UP) and HBV DNA titer. The safety endpoints were the incidence of HBV virologic breakthrough and adverse events. RESULTS: There were 14 patients in the TAC+ETV group and 17 patients in the ETV group. In the intention-to-treat analyses, 64.3% (9/14) of patients in the TAC+ETV group and 58.8% (10/17) in the ETV group achieved PR or CR at 26 weeks (P=0.38). At week 14, 42.9% (6/14) and 41.2% (7/17) of patients in the TAC+ETV group and the ETV group, respectively, achieved PR or CR (P=0.23). At week 26, the 24 h UP had decreased by 2.63±6.33 g from baseline in the TAC+ETV group and 1.42±4.34 g in the ETV group (P=0.55). The serum albumin increased by 11.1±7.30 g/L from baseline in the TAC+ETV group and 3.81±5.09 g/L in the ETV group (P<0.001). Log10 HBV DNA decreased by 1.49±2.04 from baseline in the TAC+ETV group and 2.47±2.08 in the ETV group (P=0.37); 28.6% (4/14) patients had HBV DNA virologic breakthrough in the ETV group, while none in the TAC+ETV group (P=0.29). CONCLUSIONS: In adult HBV-GN patients, TAC and ETV combination therapy may significantly improve serum albumin levels without increasing the risk of HBV reactivation compared with entecavir monotherapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03062813.

[The sensitivity and accuracy of RIFLE and AKIN criteria for acute kidney injury diagnosis in intensive care unit patients].

OBJECTIVE: To evaluate the sensitivity/accuracy of 2 different acute kidney injury (AKI) diagnosis/classification criteria, the RIFLE (risk, injury, failure, loss of kidney function, end-stage kidney disease) and the acute kidney injury network (AKIN), for patients in intensive care unit (ICU). METHODS: Clinical data were collected from all adult patients admitted to the Department of Intensive Medicine in Guangdong General Hospital between October 2009 and July 2010, and AKI cases were identified/classified using RIFLE and AKIN criteria separately, for statistical evaluation of their diagnostic sensitivity, and accuracy in hospital mortality prediction. RESULTS: In all 524 patients evaluated, AKI were identified by RIFLE criteria in 95 of them, while by AKIN, 135. The AKI incidence by RIFLE (18.1%), and AKIN (25.8%) were significantly different (P < 0.05). Meanwhile, AKI incidence was found independent from the mortality, either by RIFLE or AKIN (both P < 0.001). In all patients, the area under the receiver operator characteristic curve (ROC curve), the index for hospital mortality prediction, was 0.7293 for RIFLE [with 95% confidence interval (95%CI) ranging from 0.6005 to 0.8581, P < 0.001], and for AKIN, 0.7777 (95%CI: 0.6664 - 0.8890, P < 0.001). No significant difference was found between the total hospital mortality by the two criteria (37.9% vs. 34.1%, P > 0.05). CONCLUSION: Although AKIN criteria has higher sensitivity in AKI diagnosis, it is not different from the RIFLE criteria in predicting hospital mortality in critically ill patients.

Enhancement of photo-driven biomethanation under visible light by nano-engineering of Rhodopseudomonas palustris.

Biomethanation is of great interest as it can transform CO2 to methane under ambient conditions. In particular, genetically engineered bacterium of Rhodopseudomonas palustris showed great promise for one-step biomethanation powered by solar energy, which is attractive for CO2 fixation as well as solar energy storage. However, biomethanation with R. palustris under visible light is inefficient due to its poor visible light response. In this study, CdS quantum dots with excellent visible light response were prepared and R. palustris/CdS hybrid cells were constructed. Interestingly, this bio-nano-hybrid cells showed high cell viability without significant cell damage, and the biomethanation performance of was enhanced about ~ 79% compared to that of the bare R. palustris cells. Moreover, the effects of different parameters on the methane production of this bio-nano-hybrid cells were determined, and the methane production rate was further improved by parameter optimization. This work demonstrated an efficient approach to reinforce the biomethanation of bacteria under unfavorable light wavelength, which would be helpful to extend the light spectra for photo-driven biomethanation.

Anti-C1q antibodies and IgG subclass distribution in sera from Chinese patients with lupus nephritis.

UNLABELLED: Objective. Anti-C1q antibodies are common in sera from patients with lupus nephritis (LN) and are associated with disease activity. The current study aimed to further investigate the prevalence of serum IgG anti-C1q antibody, its subclass distribution and their clinical and pathological association in patients with LN. METHODS: Sera were collected from 150 patients with renal biopsy-proven LN, diagnosed from 2000 to 2006 in our hospital, 30 patients with systemic lupus erythematosus (SLE) without clinical evidence of renal involvement (non-renal SLE, NR-SLE) and 63 healthy donors. ELISA was used to detect serum IgG anti-C1q antibody and its subclass. Their clinical and pathological associations were further analysed. RESULTS: The prevalence of IgG anti-C1q antibody in LN (84/150, 56%) was significantly higher than that in NR-SLE (6/30, 20%) and healthy controls (3/63, 4.8%) (P < 0.005, P < 0.001, respectively). The prevalence of anti-C1q antibody in patients with diffuse proliferative renal lesions (class IV) (59/82, 71.95%) was significantly higher than that in those with non-diffuse proliferative renal lesions (class II + III) (12/26, 46.15%, P = 0.016) and class V (13/42, 30.95%, P < 0.001). The prevalence of IgG2 (60/135, 44.44%) was significantly higher than that of IgG1 (37/135, 27.41%) and IgG3 (25/135, 18.52%) (P < 0.005, P < 0.001, respectively). IgG2 was associated with the occurrence of arthritis (P < 0.05), higher serum creatinine (P < 0.05) and lower serum C3 (P < 0.05). Of the 38 LN patients with sera both in active phase and in remission, 17 were anti-C1q antibody-positive in active phase and the antibody levels decreased in all and turned to negative in 9 (52.94%) in remission. Meanwhile, the ratio of turning negative of IgG1, IgG2 and IgG3 anti-C1q was 33%(2/6), 53.85% (7/13) and 100% (7/7), respectively. CONCLUSIONS: Anti-C1q antibodies are prevalent in LN and are closely associated with diffuse proliferative lesions. IgG2 anti-C1q might be pathogenic and IgG3 anti-C1q might be a more specific biomarker for monitoring disease activity.

Podocyte injury is suppressed by 1,25-dihydroxyvitamin D via modulation of transforming growth factor-beta 1/bone morphogenetic protein-7 signalling in puromycin aminonucleoside nephropathy rats.

1. Accumulating evidence suggests that vitamin D and its analogues are renoprotective. However, the precise mechanisms and the molecular targets by which active vitamin D exerts its beneficial effects remain obscure. The objective of the present study was to evaluate the effect of active vitamin D on rats with puromycin aminonucleoside (PAN) nephropathy, a model that is characterized by predominant podocyte injury. 2. The PAN nephropathy rats were created by a single intravenous injection of 100 mg/kg PAN. Changes in renal pathology and podocyte numbers were observed. Real-time polymerase chain reaction (PCR) was performed to examine mRNA expression of nephrin, transforming growth factor (TGF)-beta1 and bone morphogenetic protein (BMP)-7. Protein expression of nephrin, TGF-beta1, BMP-7 and p-Smad2/3 and p-Smad1/5/8 was examined by immunofluorescence, immunohistochemistry and western blotting, respectively. Rats were treated with 1,25(OH)(2)D(3) by gastric gavage at a dose of 2.5 microg/kg per day, starting 2 days before PAN injection and continuing throughout the experiment. 3. A single injection of PAN induced massive proteinuria and elevated serum creatinine on Day 7, both of which were significantly suppressed by 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)). Immunofluorescence and real-time PCR of the podocyte-associated protein nephrin revealed reduced and discontinuous staining and this change was reversed by 1,25(OH)(2)D(3). In PAN nephropathy rats, TGF-beta1 and p-Smad2/3 expression was upregulated, whereas that of BMP-7 and p-Smad1/5/8 was downregulated. Treatment with 1,25(OH)(2)D(3) significantly restored BMP-7/Smad signalling while suppressing TGF-beta1/Smad signalling. 4. In conclusion, 1,25(OH)(2)D(3) can ameliorate podocyte damage and proteinuria induced by PAN. The beneficial effects of 1,25(OH)(2)D(3) on podocytes may be attributable, in part, to direct modulation of TGF-beta1/BMP-7 signalling.

Treatment selection of recurrent hepatocellular carcinoma with microvascular invasion at the initial hepatectomy.

BACKGROUND: Recurrent hepatocellular carcinoma (rHCC) patients with microvascular invasive (MVI) positive at first resection usually had poorly differentiated tumors and worse survivals. The optimal treatment for this population remains to be elucidated. METHODS: We retrospectively analyzed 319 rHCC patients with MVI-positive at first resection from June, 2009 to June, 2017. Survival and costs between curative treatments [re-resection (RR) and radiofrequency ablation (RFA)] and transarterial chemoembolization (TACE) were compared. Subgroup comparisons were made in patients in Barcelona Clinic Liver Cancer (BCLC) stage 0-A and BCLC stage B-C, respectively. A one-to-one propensity score matching (PSM) was used to diminish bias. RESULTS: In BCLC stage 0-A, 98 received RR/RFA, and 49 received TACE. The median overall survival (OS) of RR/RFA group was not reached, while the OS of TACE group was 26.3 months (P=0.001). After matching, the OS of the RR/RFA group was longer than that of the TACE group (39.5 vs. 26.3 months, P=0.045). In BCLC stage B-C, 137 patients received TACE, 11 received RR and 24 received RFA. The median OS was 29.8 months, 17.9 months and 11.1 months for RR, RFA and TACE group, respectively. No significant difference was found between RR and TACE (P=0.237) or RFA and TACE (P=0.484) after matching. Costs of the TACE group was significantly lower than that of the RR group but similar to that of the RFA group. CONCLUSION: RR/RFA provided better survival outcomes for rHCC patients with MVI-positive at first resection in selected BCLC stage 0-A. In selected BCLC stage B-C, TACE shared a similar efficacy with RR and RFA but a lower cost than RR.

Property of filler-loaded magnetic ferrite from plastic waste bottle used to treat municipal domestic sewage.

The present work investigates the properties of self-made magnetic filler from plastic waste bottle and explores a new technology approach of waste plastic resource utilization. The magnetic filler was prepared by air plasma modification and loading magnetic ferrite on the plastic strip from waste plastic bottle. The surface properties of magnetic filler were characterized by Atomic Force Microscope (AFM), contact angle system and Fourier Transform Infrared (FTIR). AFM images of original and modified plastic strip showed that low-temperature plasma treatment markedly increased the surface roughness of plastic strip. The mean roughness (Ra) of plastic strip rose from 1.116 to 5.024 nm. FTIR spectra indicated that a lot of polar oxygenic groups were introduced onto the surface of plastic by plasma modification. Modification by low-temperature plasma increased the hydrophilicity of plastic strip surface. When treatment time is 40 s, water contact angle of plastic strip surface reduced from 78.2° of original plastic strip to 25.3°. When used in bioreactor, magnetic filler had very favorable microenvironment for microorganism growth. Magnetic filler was more efficient for removing chemical oxygen demand (COD) and [Formula: see text] in sewage than nonmagnetic filler. The resource utilization of plastic wastes will become reality if the magnetic filler is applied widely.

MT1G is Silenced by DNA Methylation and Contributes to the Pathogenesis of Hepatocellular Carcinoma.

Using genome-wide screening and TCGA-based data analysis, we identified a DNA methylation-related gene named metallothionein-1G (MT1G), which may play an important role in hepatocellular carcinoma (HCC). In this study, we found that MT1G expression was silenced in 4/6 HCC cell lines and negatively related to aberrant promoter hypermethylation. Its mRNA level was restored with demethylation treatment. Moreover, MT1G downregulation at both the transcriptional and protein level was also detected in 8 pairs of clinical HCC samples compared with its expression in adjacent normal tissues. Ectopic expression of MT1G in silenced HCC cell lines inhibited colony formation, suppressed cell migration and invasion, and repressed xenograft tumor growth in nude mice. In contrast, knockdown of MT1G by short hairpin RNA showed the opposite effect on cell proliferation and the malignant phenotype. Moreover, our data showed that MT1G suppressed tumor invasion and metastasis mainly through regulating the expression of proteins in the matrix metalloproteinase family (MMP) and modulating the epithelial-mesenchymal transition (EMT) process. To our surprise, the data from TCGA showed that hypermethylation of MT1G is associated with good survival of HCC patients. In conclusion, our study demonstrated that MT1G acts as a tumor suppressor gene in HCC development, but its clinical potential in HCC requires further evaluation.

[Dental caries in children with cleft lip and/or palate in China].

OBJECTIVE: To determine the prevalence of dental caries in children with cleft lip and Palate. METHODS: A cross-sectional study was undertaken in 380 children with cleft lip and Palate and 339 children without cleft. Dental caries were measured with decayed-missing-filed-teeth index (DMFT/dmft) and the decayed-missing-filed-surface index (DMFS/dmfs). A questionnaire survey about the socio-economic conditions and lifestyles of the children's families was undertaken in the parents of the children. RESULTS: (1) The children with cleft Palates had a higher prevalence of caries and greater DMFT(S) and dmft(s) scores than the children without cleft (P < 0.05), except for those of 3 to 5 years old. (2) For the children of 3 to 5 years old, those with cleft lip and palate had significantly more caries than those with only a cleft lip or a cleft lip and alveolus (P < 0.05). The children who had surgical repairs had lower dmft(s) than those who had not (P < 0.05). CONCLUSION: (2) Chinese children with oral cleft have more dental caries than the children without cleft. (2) Children with cleft lip and palate have higher levels of dental caries than those with cleft lip alone. The children who had surgical repairs have less dental caries.

[Association of heart valve calcification with cardiovascular outcomes in patients on maintenance hemodialysis].

OBJECTIVE: To investigate the impact of heart valve calcification (HVC) on cardiovascular outcomes in patients on maintenance hemodialysis (MHD). METHODS: We enrolled 302 Chinese patients on MHD between 2009 and 2011 including 99 with HVC identified by echocardiography screening. All the patients were followed up for 2 years and survival analysis was performed with all-cause mortality, cardiovascular mortality and new onset cardiovascular events as the endpoints. Cox regression analysis was used for analyzing the impact of heart valve calcification on the cardiovascular outcomes of the patients. RESULTS: The mean age of the total patients was 58.2∓15.0 years when receiving the initial MHD, and 53.6% were male patients. The overall mortality, cardiovascular mortality and new on-set cardiovascular events in HVC and non-HVC groups were 30.3% vs 16.3%, 22.2% vs 6.9%, and 48.5% vs 25.6%, respectively (P<0.05). Kaplan-Meier survival analysis showed a significant difference in all-cause mortality (P=0.006), cardiovascular mortality (P<0.001) and new-onset cardiovascular events (P<0.001) between HVC and non-HVC groups. After adjustment, Cox regression analysis identified HVC as a risk factor for increased all-cause mortality (HR=1.88; 95%CI: 1.11-3.19), cardiovascular mortality (HR=3.47, 95%CI: 1.76-6.84) and cardiovascular events (HR=1.64, 95% CI: 1.09-2.47). CONCLUSIONS: HVC is an independent risk factor for increased cardiovascular mortality and new cardiovascular events in patients on MHD.