Roles of transforming growth factor-βsignaling in liver disease

In this editorial we expand the discussion on the article by Zhang et al published in the recent issue of the World Journal of Hepatology.We focus on the diagnostic and therapeutic targets identified on the basis of the current understanding of the molecular mechanisms of liver disease.Transforming growth factor-β(TGF-β)belongs to a structurally related cytokine super family.The family members display different time-and tissue-specific expression patterns associated with autoimmunity,inflammation,fibrosis,and tumorigenesis;and,they participate in the pathogenesis of many diseases.TGF-βand its related signaling pathways have been shown to participate in the progression of liver diseases,such as injury,inflammation,fibrosis,cirrhosis,and cancer.The often studied TGF-β/Smad signaling pathway has been shown to promote or inhibit liver fibrosis under different circumstances.Similarly,the early immature TGF-βmolecule functions as a tumor suppressor,inducing apoptosis;but,its interaction with the mitogenic molecule epidermal growth factor alters this effect,activating anti-apoptotic signals that promote liver cancer development.Overall,TGF-βsignaling displays contradictory effects in different liver disease stages.Therefore,the use of TGF-βand related signaling pathway molecules for diagnosis and treatment of liver diseases remains a challenge and needs further study.In this editorial,we aim to review the evidence for the use of TGF-βsignaling pathway molecules as diagnostic or therapeutic targets for different liver disease stages.

RESEARCH OF WAVELET TRANSFORM INSTRUMENT SYSTEM FOR SIGNAL ANALYSIS

After brief describing the Principle of wavelet transform (WT) of signals, a new signals analysis system based on wavelet transform is introduced. The design and development of the instryment of wavelet transform are described. A number of practical uses of this system demonstrate that wavelet transform system is specially functional in identifying and processing impulse, singular and non-smooth signals, so that it should be evaluated the most advanced signal analyzing system.

Spatial signalling mediated by the transforming growth factor-β signalling pathway during tooth formation

Tooth development relies on sequential and reciprocal interactions between the epithelial and mesenchymal tissues, and it is continuously regulated by a variety of conserved and specific temporal-spatial signalling pathways. It is well known that suspensions of tooth germ cells can form tooth-like structures after losing the positional information provided by the epithelial and mesenchymal tissues. However, the particular stage in which the tooth germ cells start to form tooth-like structures after losing their positional information remains unclear. In this study, we investigated the reassociation of tooth germ cells suspension from different morphological stages during tooth development and the phosphorylation of Smad2/3 in this process. Four tooth morphological stages were designed in this study. The results showed that tooth germ cells formed odontogenic tissue at embryonic day （E） 14.5, which is referred to as the cap stage, and they formed tooth-like structures at E16.5, which is referred to as the early bell stage, and E18.5, which is referred to as the late bell stage. Moreover, the transforming growth factor-β signalling pathway might play a role in this process.

Dihydroergotamine ameliorates liver fibrosis by targeting transforming growth factor β type Ⅱ receptor

BACKGROUND The transforming growth factor β(TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type Ⅱ receptor(TGFβR2), followed by the recruitment of TGFβR1 finally triggering downstream signaling pathway.AIM To find drugs targeting TGFβR2 that inhibit TGFβR1/TGFβR2 complex formation, theoretically inhibit TGFβ signaling pathway, and thereby ameliorate liver fibrosis.METHODS Food and Drug Administration-approved drugs were screened for binding affinity with TGFβR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8(CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect.RESULTS We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine(DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFβ induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFβR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFβR2 disrupted the binding of TGFβR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson’s trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver.CONCLUSION DHE alleviates liver fibrosis by binding to TGFβR2 thereby suppressing TGFβ signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.

Modal identification based on Hilbert-Huang Transform of structural response with S VD preprocessing

In recent years, Empirical mode decomposition and Hilbert spectral analysis have been combined to identify system parameters. Singular-Value Decomposition is pro- posed as a signal preprocessing technique of Hilbert-Huang Transform to extract modal parameters for closely spaced modes and low-energy components. The proposed method is applied to a simulated airplane model built in Automatic Dynamic Analysis of Mechanical Systems software. The results demonstrate that the identified modal parameters are in good agreement with the baseline model.

Anomalous signals before 2011 Tohoku-oki Mw9.1 earthquake,detected by superconducting gravimeters and broadband seismometers

The 2011 Tohoku-oki earthquake,occurred on 11 March,2011,is a great earthquake with a seismic magnitude Mw9. 1,before which an Mw7. 5 earthquake occurred. Focusing on this great earthquake event,we applied Hilbert-Huang transform（ HHT） analysis method to the one-second interval records at seven superconducting gravimeter（ SG） stations and seven broadband seismic（ BS） stations to carry out spectrum analysis and compute the energy-frequency-time distribution. Tidal effects are removed from SG data by T-soft software before the data series are transformed by HHT method. Based on HHT spectra and the marginal spectra from the records at selected seven SG stations and seven BS stations we found anomalous signals in terms of energy. The dominant frequencies of the anomalous signals are respectively about 0. 13 Hz in SG records and 0. 2 Hz in seismic data,and the anomalous signals occurred one week or two to three days prior to the event. Taking into account that in this period no typhoon event occurred,we may conclude that these anomalous signals might be related to the great earthquake event.

Effects of Haobie Yangyin Ruanjian Decoction on hepatic fibrosis induced by carbon tetrachloride in rats

AIM:To explore the anti-fibrotic effect of Haobie Yangyin Ruanjian Decoction(HYRD)on CCl4-induced hepatic fibrosis in rats and its modulation on the transforming growth factor(TGF)β-Smad signaling pathway.METHODS:Fifty-six healthy Wistar rats were randomly divided into five groups:normal control group(n=6),CCl4-induced hepatic fibrosis group(n=14) and three treatment groups(the treated rats received HYRD via oral administration at daily dosages of 8.2,2.5 and 0.82 g/kg,respectively)of HYRD(n=12,respectively).Experimental hepatic fibrosis was induced by subcutaneous injection of carbon tetrachloride solution(CCl4 dissolved in peanut oil,4:6,V/V)with 0.5 mL/100 g body weight for the first time,and then 0.3 mL/100 g body weight twice a week for 8 wk.In the former 2 wk,rats were raised by feedstuffⅠ(80% corn meal,20%lard,0.5%cholesterol).After 2 wk,they were raised by feedstuffⅡ(corn meal and 0.5% cholesterol).Except for the control group,30%alcohol solution was given orally to each rat every other day from the beginning,1 mL for each rat.Liver function parameters and hepatic hydroxyproline content were detected by chromatometry.Serum levels of hyaluronic acid(HA),typeⅣcollagen(CIV),typeⅢprecollagen(PCⅢ)and laminin(LN)were assayed with radioimmunoassay.Deposition of collagen was observed with hematoxylin-eosin staining and collagen staining.Gene expression of TGFβ1 and Smad3 were detected with real-time reverse transcriptase-polymerase chain reaction and Western blotting,respectively.RESULTS:The serum levels of alanine transaminase and aspartate transaminase were increased in the model group compared with the control group(P<0.01),and they were decreased in the three treatment groups compared with the model group.The serum levels of total protein and albumin were decreased in the model group and increased in the three treatment groups.The hepatic hydroxyproline content and serum levels of PCⅢ,HA,LN and CIV were markedly increased in the model group compared with the control group,and decreased in the treatment groups.The gene expression of TGFβ1 and Smad3 was enhanced in the model group compared with the control group,and HYRD could down regulate their expression.CONCLUSION:HYRD can inhibit hepatic fibrosis induced by CCl4 in rats,which is probably associated with its down-regulation on fibrogenic signal transduction of TGFβ-Smad pathway.

Correlation and analysis of well-log sequence with Milankovitch cycles as rulers: A case study of coal-bearing strata of late Permian in western Guizhou

Based on the well-logging data of typical wells of Zhijin,Panxian and Weining areas in western Guizhou,the well-logging data GR of late Permian coal-bearing strata were processed and wavelet transform technique was used to carry out the sequence stratigraphy division and correlation.The study mainly focuses on the controlling effects which Milankovitch had on high frequency sequence,Milankovitch cycle can be used as a ruler of sequence stratigraphy division and correlation to ensure the scientifcity and the unity of sequence stratigraphy division.According to well-logging signal of the ideal Milankovitch cycle,the corresponding relation between the wavelet scales and the cycles is determined by wavelet analysis.Through analyzing analog signals of subsequence sets to search the corresponding relation between various system tracts and the features of time-frequency,the internal features of wavelet transform scalogram could be made clearly.According to ideal model research,features of Milankovitch curves and wavelet spectrum can be seen clearly and each well can be classifed into four third-order sequences and two system tracts.At the same time Milankovitch cycle can realize the division and correlation of stratigraphic sequence in a quick and convenient way.

Association of Down-regulation of CD109 Expression with Up-expression of Smad7 in Pathogenesis of Psoriasis

Transforming growth factor（TGF）-β signaling plays an important role in the pathogenesis of psoriasis. CD109, a novel TGF-β co-receptor, which inhibits TGF-β signaling by enhancing Smad7-dependent degradation of TGF-β type Ⅰ receptor（TGF-β RⅠ）, is abnormally expressed in psoriasis. To date, the expression of Smad7 and the correlation between CD109 and Smad7 expression in psoriasis have not been fully elucidated. This study was designed to investigate the expression and the correlation of CD109 and TGF-β signaling associated proteins in psoriasis and their roles in the pathogenesis of psoriasis. Thirty-two psoriasis specimens were subjected to immunohistochemical staining for CD109, Smad7, TGF-β RⅠ and Ki67. Ten normal skin（NS） specimens served as controls. The positive expression rate（% positive cells） of Smad7 and Ki67 in psoriasis was significantly higher than in NS（62.6%±19.9% vs. 17.2%±4.4%, and 50.7%±14.3% vs. 19.5%±3.2%, respectively, P〈0.001）, and the expression levels of CD109 and TGF-β RⅠ were reduced significantly in psoriasis as compared with NS（8.1%±6.7% vs. 35.8%±6.7% and 27.3%±3.4% vs. 3.0%±3.4%, respectively, P〈0.001）. There were significantly negative correlations between CD109 and Smad7（r=-0.831, P〈0.01）. These findings indicated that CD109 might play a certain role in the pathogenesis of psoriasis. Lower expression of CD109 and TGF-β RⅠ was highly correlated with higher expression of Smad7 and Ki67, suggesting that CD109 may induce the pathogenesis of psoriasis through Smad7-mediated degradation of TGF-β RⅠ, and lead to the termination of TGF-β signaling.

A WT-STFT combining Algorithm

A fast wavelet packet (WP) algorithm is presented, in which the wavelet transform (WT) and the short-time Fourier transform (STFT) are combined. As WT produces multiresolution of frequency and time, and STFT has a fast algorithm, the combining algorithm is suitable for fast signal analysis.

Identification of WWTR1 as an immune infiltration-correlated prognostic biomarker in colon cancer

WWTR1,a gene related to the TGF-βsignaling pathway,has been elucidated to be involved in oncogenesis in multiple studies.There is,however,no research on its link to immune infiltration in colon cancer.The TCGA database has identified WWTR1,a gene related to the TGF-βsignaling pathway,which is lowly expressed in colon cancer patients compared to normal subjects.Meanwhile,we produced the Kapan-Meier curve with GEO and the TCGA database,which revealed that colon cancer patients with high WWTR1 expression had a poor prognosis.We discovered that high expression of WWTR1 in colon cancer was associated with clinical stage,pathological T-stage,and lymphatic metastasis after examining the clinical characteristics of colon cancer patients.WWTR1 was found to be an independent predictive factor for colon cancer in a multivariate Cox regression study.Infiltration of immunological cells(B cells,CD8^(+)T cells,CD4^(+)T cells,Macrophage,Neutrophil,Dendritic cells)was linked to WWTR1 expression.In colon cancer,WWTR1 expression was also found to be favorably linked with major immune cell markers.According to an analysis of WWTR1 DCGs,GO,and KEGG enrichment analysis,WWTR1 expression levels were associated with ameboidal-type cell migration,focal adhesion,actin binding,Chemical carcinogenesis-reactive oxygen species,Non-alcoholic fatty liver disease,and Alzheimer disease.These findings imply that WWTR1 is a prognostically valuable and important biomarker for colon cancer,and imply that its expression is strongly linked to colon cancer immune infiltration,making it a potential new target for colon cancer biotherapy.

Effect of ursodeoxycholic acid on TGF betal/Smad signaling pathway in rat hepatic stellate cells

Background Hepatic fibrosis is the key stage of the pathological progress from hepatic injury to cirrhosis. Ursodeoxycholic acid （UDCA） has been known as having significant clinical therapeutic effects on chronic liver diseases. Our research aimed to study the effect of UDCA on the signaling pathway of transforming growth factor beta1 （TGFβ1）/Smad and discuss its possible molecular mechanisms of inhibiting hepatic fibrosis. Methods Rat hepatic stellate cells were cultured in vitro and randomly assigned to 4 groups. Group A was control group with only DMEM culture medium applied, and groups B, C, D were experimental groups, with different doses of UDCA （1.0 mmol/L, 0.5 mmol/L and 0.25 mmol/L respectively） added into their DMEM culture medium for further culture of 24 hours and 48 hours. The protein expressions of TGFβ1, TGF type 1 receptor, Smad3, Smad4 and Smad7 were measured by Western blotting, as well as the expressions of TGFβ1, Smad3, Smad7 and cAMP response element （CREB） binding protein （CBP） mRNA by real-time PCR. SPSS 11.5 statistical package was adopted for data analyses. Results Compared with control group, the mRNA expressions of TGFβ1 in the high and middle UDCA dose groups for 24 hours and 48 hours significantly decreased （P 〈0.05）, the protein expressions of TGFβ1 in the two above groups for 48 hours and in the high dose group for 24 hours significantly decreased （P 〈0.05）. The protein and mRNA expressions of Smad3 in each UDCA dose group for 24 hours and 48 hours significantly decreased, with significant difference among different UDCA dose groups and between that of 24 hours and 48 hours observed （P 〈0.05）. The protein and mRNA expressions of Smad7 in the high and middle UDCA dose groups for 24 hours and 48 hours significantly increased. The CBP mRNA expression in each UDCA dose group for 24 hours and 48 hours significantly decreased （P 〈0.05）, with significant difference among different UDCA dose groups observed （P 〈0.05）. Conclusion UDCA could curb the development of hepatic fibrosis through affecting the signaling pathway of TGFβ1/Smad by inhibiting the expressions of TGFβ1, Smad3 and CBP and increasing the expression of Smad7.

An approach for parameter estimation of combined CPPM and LFM radar signal

In this paper, the problem of parameter estimation of the combined radar signal adopting chaotic pulse position modulation （CPPM） and linear frequency modulation （LFM）, which can be widely used in electronic countermeasures, is addressed. An approach is proposed to estimate the initial frequency and chirp rate of the combined signal by exploiting the second-order cyclostationarity of the intra-pulse signal. In addition, under the condition of the equal pulse width, the pulse repetition interval （PRI） of the combined signal is predicted using the low-order Volterra adaptive filter. Simulations demonstrate that the proposed cyclic autocorrelation Hough transform （CHT） algorithm is theoretically tolerant to additive white Gaussian noise. When the value of signal noise to ratio （SNR） is less than 4 dB, it can still estimate the intra-pulse parameters well. When SNR = 3 dB, a good prediction of the PRI sequence can be achieved by the Volterra adaptive filter algorithm, even only 100 training samples.

Modified fast Fourier transform in FBMC for satellite communications

In this paper,a Doppler scaling fast Fourier transform（Doppler-FFT）algorithm for filter bank multi-carrier（FBMC）is proposed,which can efficiently eliminate the impact of the Doppler scaling in satellite communications.By introducing a Doppler scaling factor into the butterfly structure of the fast Fourier transform（FFT）algorithm,the proposed algorithm eliminates the differences between the Doppler shifts of the received subcarriers,and maintains the same order of computational complexity compared to that of the traditional FFT.In the process of using the new method,the Doppler scaling should be estimated by calculating the orbital data in advance.Thus,the inter-symbol interference（ISI）and the inter-carrier interference（ICI）can be completely eliminated,and the signal to interference and noise ratio（SINR）will not be affected.Simulation results also show that the proposed algorithm can achieve a 0.4 d B performance gain compared to the frequency domain equalization（FDE）algorithm in satellite communications.

Qingxuan Jiangya Decoction(清眩降压汤) Prevents Blood Pressure Elevation and Ameliorates Vascular Structural Remodeling via Modulating TGF-β 1/Smad Pathway in Spontaneously Hypertensive Rats

Objective:To elevate the effects of Qingxuan Jiangya Decoction(清眩降压汤,QXJYD)on hypertension and vascular structural remodeling(VSR)in spontaneously hypertensive rats(SHRs),and investigate the underlying mechanisms.Methods:SHRs(n=8)were given intra-gastric administration with 60 mg/kg of QXJYD or saline,daily for 8 weeks,while rats in SHR-control(n=8)and WKY(n=8)groups were received equal volumes of saline solution.Systolic blood pressures(SBP),diastolic blood pressures(DBP)and mean blood pressures(MBP)were measured once a week.The levels of angiotensinⅡ(AngⅡ),endothelin 1(ET-1)and plasma renin activity(PRA)were tested by enzyme-linked immunosorbent assay(ELISA)and radioimmunoassay,respectively.The effect of QXJYD on VSR was determined by examining the media thickness and the ex vivo contractility of thoracic aortic.The proliferation and fibrosis of vascular smooth muscle cells(VSMCs)were examined via immunohistochemical(IHC)staining for proliferating cell nuclear antigen(PCNA),collagen Ⅰ and collagen Ⅲ,respectively.The mRNA and protein expressions of transforming growth factor β1(TGF-β1),Smad3 and phosphorylation of Smad3 in thoracic aorta tissues were determined by real-time polymerase chain reaction(PCR)and Western blot assay,respectively.Results:QXJYD treatment led to a significant decrease of the elevation of blood pressure in SHRs and reduced the levels of AngⅡ,ET-1 and PRA in the serum(P<0.05).In addition,QXJYD treatment remarkably ameliorated VSR and vascular function in SHRs.Moreover,QXJYD inhibited VSMC proliferation and fibrosis by suppressing the expression of PCNA,collagen Ⅰ and collagen Ⅲ in thoracic aortic.Furthermore,QXJYD inhibited the expression of TGF-β1,Smad3 and the phosphorylation of Smad3,respectively(P<0.05).Conclusion:QXJYD reversed VSR by inhibiting VSMC proliferation and collagen deposition via regulation of TGF-β1/Smad signaling pathway,which may,in part,illuminate its anti-hypertensive activities.