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author:("Chen, wiping")
1.  Nephrokeli, a Chinese Herbal Formula, May Improve IgA Nephropathy through Regulation of the Sphingosine-1-Phosphate Pathway 
PLoS ONE  2015;10(1):e0116873.
Nephrokeli (NPKL) is a Chinese herbal formula that has been used to treat patients with IgA nephropathy (IgAN) for improvement of proteinuria and kidney injury. However, the mechanism remains unclear. Sphingosine-1-phosphate (S1P) and its receptors S1PR2 and S1PR3 are known to play an important role in kidney disease. Here, we tested whether NPKL is able to regulate the S1P pathway in the kidney of IgAN rats. Four groups of rats were included in the study: Control, IgAN, IgAN treated with losartan, and IgAN treated with NPKL. The IgAN model was generated by injection of bovine serum albumin and staphylococcus enterotoxin B. We found that IgAN rats had increased staining for proliferating cell nuclear antigen (PCNA) in the mesangial area and increased mRNA and protein levels of S1PR2 and S1PR3 in the kidney compared to control rats. Connective tissue growth factor (CTGF), a downstream growth factor in the S1P pathway, was also elevated in the kidney of IgAN rats. Treatment with either NPKL or losartan was able to reduce PCNA staining and the expression of both S1PR2 and S1PR3 in the kidney of IgAN rats. However, NPKL (but not losartan treatment) reduced the expression of CTGF in the kidney of IgAN rats. In addition, we treated rat mesangial cells with sera collected from either NPKL-treated rats or control rats and found that NPKL-serum was able to reduce S1P-induced mesangial cell proliferation and the expression of S1PR2/S1PR3 and CTGF. NPKL also attenuates expression of fibrosis, inflammation, and oxidative stress markers in the kidney of IgAN rats. Our studies provide the mechanism by which NPKL attenuates kidney injury in IgAN rats.
PMCID: PMC4310606  PMID: 25633986
2.  Depression, anxiety, and prevalent diabetes in the Chinese population: Findings from the China Kadoorie Biobank of 0.5 million people 
Journal of psychosomatic research  2013;75(6):511-517.
Despite previous investigation, uncertainty remains about the nature of the associations of major depression (MD) with type 2 diabetes mellitus (T2DM), particularly in adult Chinese, and the relevance of generalized anxiety disorder (GAD) for T2DM.
Cross-sectional data from the China Kadoorie Biobank Study, a sample of approximately 500,000 adults from 10 geographically defined regions of China, were analyzed. Past year MD and GAD were assessed using the Composite International Diagnostic Inventory. T2DM was defined as either having self-reported physician diagnosis of diabetes at age 30 or later (“clinically-identified” cases) or having a non-fasting blood glucose ≥11.1 mmol/L or fasting blood glucose ≥7.0 mmol/L but no prior diagnosis of diabetes (“screen-detected” cases). Logistic regression was used to assess the relationship between MD and GAD with clinically-identified and screen-detected T2DM, adjusting for demographic characteristics and health behaviors.
The prevalence of T2DM was 5.3% (3.2% clinically-identified and 2.1% screen-detected). MD was significantly associated with clinically-identified T2DM (Odds ratio [OR]: 1.75, 95% Confidence Interval (CI): 1.47 – 2.08), but not with screen-detected T2DM (OR: 1.18, 95% CI: 0.92 – 1.51). GAD was associated with both clinically-identified (OR: 2.14, 95% CI: 1.60 – 2.88) and screen-detected (OR: 1.44, 95% CI: 0.99 – 2.08) T2DM. The relationship between MD and GAD with T2DM was moderated by obesity.
MD is associated with clinically-identified, but not screen-detected T2DM. GAD is associated with both clinically-identified and screen-detected T2DM. The relationship between MD and T2DM is strongest among those who are not obese.
PMCID: PMC3919064  PMID: 24290039
anxiety; culture; depression; epidemiology; type 2 diabetes
3.  BMP-FGF Signaling Axis Mediates Wnt-Induced Epidermal Stratification in Developing Mammalian Skin 
PLoS Genetics  2014;10(10):e1004687.
Epidermal stratification of the mammalian skin requires proliferative basal progenitors to generate intermediate cells that separate from the basal layer and are replaced by post-mitotic cells. Although Wnt signaling has been implicated in this developmental process, the mechanism underlying Wnt-mediated regulation of basal progenitors remains elusive. Here we show that Wnt secreted from proliferative basal cells is not required for their differentiation. However, epidermal production of Wnts is essential for the formation of the spinous layer through modulation of a BMP-FGF signaling cascade in the dermis. The spinous layer defects caused by disruption of Wnt secretion can be restored by transgenically expressed Bmp4. Non-cell autonomous BMP4 promotes activation of FGF7 and FGF10 signaling, leading to an increase in proliferative basal cell population. Our findings identify an essential BMP-FGF signaling axis in the dermis that responds to the epidermal Wnts and feedbacks to regulate basal progenitors during epidermal stratification.
Author Summary
Epidermis, a thin layer of stratified epithelium forming the outmost surface of the skin, provides the crucial function to protect animals from environmental insults, such as bacterial pathogens and water loss. This barrier function is established in embryogenesis, during which single layered epithelial cells differentiate into distinct layers of keratinocytes. Many human genetic diseases are featured with epidermal disruption, affecting at least one in five patients. Skin regeneration and future therapeutics require a thorough understanding of the molecular mechanisms underlying epidermal stratification. Wnt ligands have been implicated in hair follicle induction during skin development and self-renewal of stem cells in the interfollicular epidermis of adult skin; however, little is known about the mechanism of how Wnt signaling controls epidermal stratification during embryogenesis. In this study, by using a genetic mouse model to disrupt Wnt production in skin development, we found that signaling of epidermal Wnt in the dermis initiate mesenchymal responses by activating a Bone Morphogenetic Protein (BMP) and Fibroblast growth factor (FGF) signaling cascade, and this activation is required for feedback regulations in the embryonic epidermis to control stratification. Our findings identify a genetic hierarchy of signaling essential for epidermal-mesenchymal interactions, and promote our understanding of mammalian skin development.
PMCID: PMC4199507  PMID: 25329657
4.  Enhanced BMP signaling prevents degeneration and leads to endochondral ossification of Meckel’s cartilage in mice 
Developmental biology  2013;381(2):301-311.
Meckel’s cartilage is a transient supporting tissue of the embryonic mandible in mammals, and disappears by taking different ultimate cell fate along the distal-proximal axis, with the majority (middle portion) undergoing degeneration and chondroclastic resorption. While a number of factors have been implicated in the degeneration and resorption processes, signaling pathways that trigger this degradation are currently unknown. BMP signaling has been implicated in almost every step of chondrogenesis. In this study, we used Noggin mutant mice as a model for gain-of-BMP signaling function to investigate the function of BMP signaling in Meckel’s cartilage development, with a focus on the middle portion. We showed that Bmp2 and Bmp7 are expressed in early developing Meckels’ cartilage, but their expression disappears thereafter. In contrast, Noggin is expressed constantly in Meckel’s cartilage throughout the entire gestation period. In the absence of Noggin, Meckel’s cartilage is significantly thickened attributing to dramatically elevated cell proliferation rate associated with enhanced phosphorylated Smad1/5/8 expression. Interestingly, instead of taking a degeneration fate, the middle portion of Meckel’s cartilage in Noggin mutants undergoes chondrogenic differentiation and endochondral ossification contributing to the forming mandible. Chondrocyte-specific expression of a constitutively active form of BMPRIa but not BMPRIa leads enlargement of Meckel’s cartilage, phenocopying the consequence of Noggin deficiency. Our results demonstrate that elevated BMP signaling prevents degeneration and leads to endochondral ossification of Meckel’s cartilage, and support the idea that withdrawal of BMP signaling is required for normal Meckel’s cartilage development and ultimate cell fate.
PMCID: PMC3777720  PMID: 23891934
BMP signaling; Noggin; BmprIa; Meckel’s cartilage; development; differentiation
5.  Smoking and Major Depressive Disorder in Chinese Women 
PLoS ONE  2014;9(9):e106287.
To investigate the risk factors that contribute to smoking in female patients with major depressive disorder (MDD) and the clinical features in depressed smokers.
We examined the smoking status and clinical features in 6120 Han Chinese women with MDD (DSM-IV) between 30 and 60 years of age across China. Logistic regression was used to determine the association between clinical features of MDD and smoking status and between risk factors for MDD and smoking status.
Among the recurrent MDD patients there were 216(3.6%) current smokers, 117 (2.0%) former smokers and 333(5.6%) lifetime smokers. Lifetime smokers had a slightly more severe illness, characterized by more episodes, longer duration, more comorbid illness (panic and phobias), with more DSM-IV A criteria and reported more symptoms of fatigue and suicidal ideation or attempts than never smokers. Some known risk factors for MDD were also differentially represented among smokers compared to non-smokers. Smokers reported more stressful life events, were more likely to report childhood sexual abuse, had higher levels of neuroticism and an increased rate of familial MDD. Only neuroticism was significantly related to nicotine dependence.
Although depressed women smokers experience more severe illness, smoking rates remain low in MDD patients. Family history of MDD and environmental factors contribute to lifetime smoking in Chinese women, consistent with the hypothesis that the association of smoking and depression may be caused by common underlying factors.
PMCID: PMC4152240  PMID: 25180682
6.  Exploring the effects of gene dosage on mandible shape in mice as a model for studying the genetic basis of natural variation 
Development genes and evolution  2013;223(5):279-287.
Mandible shape in the mouse is a complex trait that is influenced by many genetic factors. However, little is known about the action of single genes on adult mandible shape so far, since most developmentally relevant genes are already required during embryogenesis, i.e. knockouts lead to embryonic death or severe deformations, before the mandible is fully formed. We employ here a geometric morphometrics approach to identify subtle phenotypic differences caused by dosage effects of candidate genes. We use mouse strains with specific gene modifications (knock-outs and knock-ins) to compare heterozygous animals with controls from the same stock, which is expected to be equivalent to a change of gene expression of the respective locus. Such differences in expression level are also likely to occur as part of the natural variation. We focus on Bmp pathway genes (Bmp4, its antagonist Noggin and combinations of Bmp5–7 genotypes), but include also two other developmental control genes suspected to affect mandible development in some way (Egfr and Irf6). In addition, we study effects of Hoxd13, as well as an extracellular matrix constituent (Col2a1). We find that subtle, but significant shape differences are caused by differences in gene dosage of several of these genes. The changes seen for Bmp4 and Noggin are partially compatible with the action of these genes known from birds and fish. We find significant shape changes also for Hoxd13, although this gene has so far only been implicated in skeletal patterning processes of the limbs. Comparing the effect sizes of gene dosage changes to the variation found in natural populations of mice as well as QTL effects on mandible shape, we find that the effect sizes caused by gene dosage changes are at the lower end of the spectrum of natural variation, but larger than the average additive effects found in QTL studies. We conclude that studying gene dosage effects have the potential to provide new insights into aspects of craniofacial development, variation and evolution.
PMCID: PMC4013528  PMID: 23563729
shape analysis; morphometry; dosage effects; mandible development; Mus musculus
7.  BMPRIA Mediated Signaling Is Essential for Temporomandibular Joint Development in Mice 
PLoS ONE  2014;9(8):e101000.
The central importance of BMP signaling in the development and homeostasis of synovial joint of appendicular skeleton has been well documented, but its role in the development of temporomandibular joint (TMJ), also classified as a synovial joint, remains completely unknown. In this study, we investigated the function of BMPRIA mediated signaling in TMJ development in mice by transgenic loss-of- and gain-of-function approaches. We found that BMPRIA is expressed in the cranial neural crest (CNC)-derived developing condyle and glenoid fossa, major components of TMJ, as well as the interzone mesenchymal cells. Wnt1-Cre mediated tissue specific inactivation of BmprIa in CNC lineage led to defective TMJ development, including failure of articular disc separation from a hypoplastic condyle, persistence of interzone cells, and failed formation of a functional fibrocartilage layer on the articular surface of the glenoid fossa and condyle, which could be at least partially attributed to the down-regulation of Ihh in the developing condyle and inhibition of apoptosis in the interzone. On the other hand, augmented BMPRIA signaling by Wnt1-Cre driven expression of a constitutively active form of BmprIa (caBmprIa) inhibited osteogenesis of the glenoid fossa and converted the condylar primordium from secondary cartilage to primary cartilage associated with ectopic activation of Smad-dependent pathway but inhibition of JNK pathway, leading to TMJ agenesis. Our results present unambiguous evidence for an essential role of finely tuned BMPRIA mediated signaling in TMJ development.
PMCID: PMC4122352  PMID: 25093411
8.  Pten loss induces autocrine FGF signaling to promote skin tumorigenesis 
Cell reports  2014;6(5):818-826.
Inactivation of the Pten tumor suppressor negatively regulates the PI3K-mTOR pathway. In a model of cutaneous squamous cell carcinoma (SCC), we demonstrate that deletion of Pten strongly elevates Fgf10 protein levels without increasing Fgf10 transcription in vitro and in vivo. The translational activation of Fgf10 by Pten deletion is reversed by genetic disruption of the mTORC1 complex, which also prevents skin tumorigenesis in Pten mutants. We further show that ectopic expression of Fgf10 causes skin papillomas, while Pten deletion-induced skin tumors are inhibited by epidermal deletion of Fgfr2. Collectively, our data identify autocrine activation of FGF signaling as an essential mechanism in promoting Pten-deficient skin tumors.
PMCID: PMC4080841  PMID: 24582960
9.  A Compact Methodology to Understand, Evaluate, and Predict the Performance of Automatic Target Recognition 
Sensors (Basel, Switzerland)  2014;14(7):11308-11350.
This paper offers a compacted mechanism to carry out the performance evaluation work for an automatic target recognition (ATR) system: (a) a standard description of the ATR system's output is suggested, a quantity to indicate the operating condition is presented based on the principle of feature extraction in pattern recognition, and a series of indexes to assess the output in different aspects are developed with the application of statistics; (b) performance of the ATR system is interpreted by a quality factor based on knowledge of engineering mathematics; (c) through a novel utility called “context-probability” estimation proposed based on probability, performance prediction for an ATR system is realized. The simulation result shows that the performance of an ATR system can be accounted for and forecasted by the above-mentioned measures. Compared to existing technologies, the novel method can offer more objective performance conclusions for an ATR system. These conclusions may be helpful in knowing the practical capability of the tested ATR system. At the same time, the generalization performance of the proposed method is good.
PMCID: PMC4168426  PMID: 24967605
automatic target recognition; performance evaluation; performance prediction
10.  Therapeutic use of traditional Chinese herbal medications for chronic kidney diseases 
Kidney international  2013;84(6):10.1038/ki.2013.276.
Traditional Chinese herbal medications (TCHM) are frequently used in conjunction with western pharmacotherapy for treatment of chronic kidney diseases (CKD) in China and many other Asian countries. The practice of traditional Chinese medicine is guided by cumulative empiric experience. Recent in vitro and animal studies have confirmed the biological activity and therapeutic effects of several TCHM in CKD. However, the level of evidence supporting TCHM is limited to small, non-randomized trials. Due to variations in the prescription pattern of TCHM and the need for frequent dosage adjustment, which are inherent to the practice of traditional Chinese medicine, it has been challenging to design and implement large randomized clinical trials of TCHM. Several TCHM are associated with significant adverse effects, including nephrotoxicity. However, reporting of adverse effects associated with TCHM has been inadequate. To fully realize the therapeutic use of TCHM in CKD we need molecular studies to identify active ingredients of TCHM and their mechanism of action, rigorous pharmacologic studies to determine the safety and meet regulatory standards required for clinical therapeutic agents, and well-designed clinical trials to provide evidence-based support of their safety and efficacy.
PMCID: PMC3812398  PMID: 23868014
Kidney disease; Chinese herb medications; toxicity; alternative medicine; drug discovery
11.  Phosphorylation of Shox2 Is Required for Its Function to Control Sinoatrial Node Formation 
Inactivation of Shox2, a member of the short‐stature homeobox gene family, leads to defective development of multiple organs and embryonic lethality as a result of cardiovascular defects, including bradycardia and severe hypoplastic sinoatrial node (SAN) and sinus valves, in mice. It has been demonstrated that Shox2 regulates a genetic network through the repression of Nkx2.5 to maintain the fate of the SAN cells. However, the functional mechanism of Shox2 protein as a transcriptional repressor on Nkx2.5 expression remains completely unknown.
Methods and Results
A specific interaction between the B56δ regulatory subunit of PP2A and Shox2a, the isoform that is expressed in the developing heart, was demonstrated by yeast 2‐hybrid screen and coimmunoprecipitation. Western blotting and immunohistochemical assays further confirmed the presence of phosphorylated Shox2a (p‐Shox2a) in cell culture as well as in the developing mouse and human SAN. Site‐directed mutagenesis and in vitro kinase assays identified Ser92 and Ser110 as true phosphorylation sites and substrates of extracellular signal‐regulated kinase 1 and 2. Despite that Shox2a and its phosphorylation mutants possessed similar transcriptional repressive activities in cell cultures when fused with Gal4 protein, the mutant forms exhibited a compromised repressive effect on the activity of the mouse Nkx2.5 promoter in cell cultures, indicating that phosphorylation is required for Shox2a to repress Nkx2.5 expression specifically. Transgenic expression of Shox2a, but not Shox2a‐S92AS110A, mutant in the developing heart resulted in down‐regulation of Nkx2.5 in wild‐type mice and rescued the SAN defects in the Shox2 mutant background. Last, we demonstrated that elimination of both phosphorylation sites on Shox2a did not alter its nuclear location and dimerization, but depleted its capability to bind to the consensus sequences within the Nkx2.5 promoter region.
Our studies reveal that phosphorylation is essential for Shox2a to repress Nkx2.5 expression during SAN development and differentiation.
PMCID: PMC4309068  PMID: 24847033
DNA binding; Nkx2.5 repression; pacemaking; phosphorylation; SAN development; Shox2
12.  Bioengineering of a human whole tooth: progress and challenge 
Cell Regeneration  2014;3(1):8.
A major challenge in stem cell-based bioengineering of an implantable human tooth is to identify appropriate sources of postnatal stem cells that are odontogenic competent as the epithelial component due to the lack of enamel epithelial cells in adult teeth. In a recent issue (2013, 2:6) of Cell Regeneration, Cai and colleagues reported that epithelial sheets derived from human induced pluripotent stem cells (iPSCs) can functionally substitute for tooth germ epithelium to regenerate tooth-like structures, providing an appealing stem cell source for future human tooth regeneration.
PMCID: PMC4230350  PMID: 25408887
13.  Use of drug treatment for secondary prevention of cardiovascular disease in urban and rural communities of China: China Kadoorie Biobank Study of 0.5 million people☆ 
Relatively little is known about the use of medication for the secondary prevention of cardiovascular disease (CVD) events in China, and the relevance to it of socioeconomic, lifestyle and health-related factors.
Methods and results
We analysed cross-sectional data from the China Kadoorie Biobank (CKB) of 512,891 adults aged 30–79 years recruited from 1737 rural and urban communities in China. Information about doctor-diagnosed ischaemic heart disease (IHD) and stroke, and the use of medication for the secondary prevention of CVD events, were recorded by interview. Multivariate logistic regression was used to estimate odds ratios (ORs) for use of secondary preventive treatment, adjusting simultaneously for age, sex, area and education. Overall, 23,129 (4.5%) participants reported a history of CVD (3.0% IHD, 1.7% stroke). Among them, 35% reported current use of any of 6 classes of drug (anti-platelet, statins, diuretics, ACE-I, β-blockers or calcium-channel blockers) for the prevention of CVD events, with the rate of usage greater in those with older age, higher levels of income, education, BMI or blood pressure. The use of these agents was associated positively with history of diagnosed hypertension (OR 7.5; 95% confidence intervals: 7.08–8.06) and diabetes (1.40; 1.28–1.52) and inversely with self-rated health status, but there was no association with years since diagnosis.
Despite recent improvements in hospital care in China, only one in three individuals with prior CVD was routinely treated with any proven secondary preventive drugs. The treatment rates were correlated with the existence of other risk factors, in particular evidence of hypertension.
PMCID: PMC3991854  PMID: 24461961
Ischemic heart disease; Stroke; Secondary prevention; Cardiovascular medication; Rural and urban communities; China
14.  Associations of Educational Attainment, Occupation, Social Class and Major Depressive Disorder among Han Chinese Women 
PLoS ONE  2014;9(1):e86674.
The prevalence of major depressive disorder (MDD) is higher in those with low levels of educational attainment, the unemployed and those with low social status. However the extent to which these factors cause MDD is unclear. Most of the available data comes from studies in developed countries, and these findings may not extrapolate to developing countries. Examining the relationship between MDD and socio economic status in China is likely to add to the debate because of the radical economic and social changes occurring in China over the last 30 years.
Principal findings
We report results from 3,639 Chinese women with recurrent MDD and 3,800 controls. Highly significant odds ratios (ORs) were observed between MDD and full time employment (OR = 0.36, 95% CI = 0.25–0.46, logP = 78), social status (OR = 0.83, 95% CI = 0.77–0.87, logP = 13.3) and education attainment (OR = 0.90, 95% CI = 0.86–0.90, logP = 6.8). We found a monotonic relationship between increasing age and increasing levels of educational attainment. Those with only primary school education have significantly more episodes of MDD (mean 6.5, P-value = 0.009) and have a clinically more severe disorder, while those with higher educational attainment are likely to manifest more comorbid anxiety disorders.
In China lower socioeconomic position is associated with increased rates of MDD, as it is elsewhere in the world. Significantly more episodes of MDD occur among those with lower educational attainment (rather than longer episodes of disease), consistent with the hypothesis that the lower socioeconomic position increases the likelihood of developing MDD. The phenomenology of MDD varies according to the degree of educational attainment: higher educational attainment not only appears to protect against MDD but alters its presentation, to a more anxious phenotype.
PMCID: PMC3909008  PMID: 24497966
15.  Childhood Sexual Abuse and the Development of Recurrent Major Depression in Chinese Women 
PLoS ONE  2014;9(1):e87569.
Our prior study in Han Chinese women has shown that women with a history of childhood sexual abuse (CSA) are at increased risk for developing major depression (MD). Would this relationship be found in our whole data set?
Three levels of CSA (non-genital, genital, and intercourse) were assessed by self-report in two groups of Han Chinese women: 6017 clinically ascertained with recurrent MD and 5983 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression.
We confirmed earlier results by replicating prior analyses in 3,950 new recurrent MD cases. There were no significant differences between the two data sets. Any form of CSA was significantly associated with recurrent MD (OR 4.06, 95% confidence interval (CI) [3.19–5.24]). This association strengthened with increasing CSA severity: non-genital (OR 2.21, 95% CI 1.58–3.15), genital (OR 5.24, 95% CI 3.52–8.15) and intercourse (OR 10.65, 95% CI 5.56–23.71). Among the depressed women, those with CSA had an earlier age of onset, longer depressive episodes. Recurrent MD patients those with CSA had an increased risk for dysthymia (OR 1.60, 95%CI 1.11–2.27) and phobia (OR 1.41, 95%CI 1.09–1.80). Any form of CSA was significantly associated with suicidal ideation or attempt (OR 1.50, 95% CI 1.20–1.89) and feelings of worthlessness or guilt (OR 1.41, 95% CI 1.02–2.02). Intercourse (OR 3.47, 95%CI 1.66–8.22), use of force and threats (OR 1.95, 95%CI 1.05–3.82) and how strongly the victims were affected at the time (OR 1.39, 95%CI 1.20–1.64) were significantly associated with recurrent MD.
In Chinese women CSA is strongly associated with recurrent MD and this association increases with greater severity of CSA. Depressed women with CSA have some specific clinical traits. Some features of CSA were associated with greater likelihood of developing recurrent MD.
PMCID: PMC3906190  PMID: 24489940
16.  Puerarin Attenuated Early Diabetic Kidney Injury through Down-Regulation of Matrix Metalloproteinase 9 in Streptozotocin-Induced Diabetic Rats 
PLoS ONE  2014;9(1):e85690.
Radix puerariae, a traditional Chinese herbal medication, has been used successfully to treat patients with early stage of diabetic nephropathy. However, the underlined mechanism of this renal protective effect has not been determined. In the current study, we investigated the effects and the mechanism of puerarin in Streptozotocin (STZ)-induced diabetic rats. We treated STZ-rats with either puerarin or losartan, an angiotensin II receptor blocker, as compared to those treated with vehicle. We found that both puerarin and losartan attenuated kidney hypertrophy, mesangial expansion, proteinuria, and podocyte foot process effacement in STZ rats. In addition, both puerarin and losartan increased expression of podocyte slit diaphragm proteins such as nephrin and podocin. Interestingly, we found that puerarin treatment induced a more pronounced suppression of oxidative stress production and S-nitrosylation of proteins in the diabetic kidneys as compared to losartan treatment. Furthermore, we found that matrix metalloproteinase-9 (MMP-9), which is known to be activated by oxidative stress and S-nitrosylation of proteins, was also suppressed more extensively by puerarin than losartan. In conclusion, these data provide for the first time the potential mechanism to support the use of puerarin in the treatment of early diabetic nephropathy.
PMCID: PMC3893265  PMID: 24454919
17.  Clinical Features of Patients with Dysthymia in a Large Cohort of Han Chinese Women with Recurrent Major Depression 
PLoS ONE  2013;8(12):e83490.
Dysthymia is a form of chronic mild depression that has a complex relationship with major depressive disorder (MDD). Here we investigate the role of environmental risk factors, including stressful life events and parenting style, in patients with both MDD and dysthymia. We ask whether these risk factors act in the same way in MDD with and without dysthymia.
We examined the clinical features in 5,950 Han Chinese women with MDD between 30–60 years of age across China. We confirmed earlier results by replicating prior analyses in 3,950 new MDD cases. There were no significant differences between the two data sets. We identified sixteen stressful life events that significantly increase the risk of dysthymia, given the presence of MDD. Low parental warmth, from either mother or father, increases the risk of dysthymia. Highly threatening but short-lived threats (such as rape) are more specific for MDD than dysthymia. While for MDD more severe life events show the largest odds ratio versus controls, this was not seen for cases of MDD with or without dysthymia.
There are increased rates of stressful life events in MDD with dysthymia, but the impact of life events on susceptibility to dysthymia with MDD differs from that seen for MDD alone. The pattern does not fit a simple dose-response relationship, suggesting that there are moderating factors involved in the relationship between environmental precipitants and the onset of dysthymia. It is possible that severe life events in childhood events index a general susceptibility to chronic depression, rather than acting specifically as risk factors for dysthymia.
PMCID: PMC3873934  PMID: 24386213
18.  Suicidal Risk Factors of Recurrent Major Depression in Han Chinese Women 
PLoS ONE  2013;8(11):e80030.
The relationship between suicidality and major depression is complex. Socio- demography, clinical features, comorbidity, clinical symptoms, and stressful life events are important factors influencing suicide in major depression, but these are not well defined. Thus, the aim of the present study was to assess the associations between the above-mentioned factors and suicide ideation, suicide plan, and suicide attempt in 6008 Han Chinese women with recurrent major depression (MD). Patients with any suicidality had significantly more MD symptoms, a significantly greater number of stressful life events, a positive family history of MD, a greater number of episodes, a significant experience of melancholia, and earlier age of onset. Comorbidity with dysthymia, generalized anxiety disorder (GAD), social phobia, and animal phobia was seen in suicidal patients. The present findings indicate that specific factors act to increase the likelihood of suicide in MD. Our results may help improve the clinical assessment of suicide risk in depressed patients, especially for women.
PMCID: PMC3842272  PMID: 24312196
19.  Discrepant findings in immune responses to JC virus in patients receiving natalizumab 
Lancet neurology  2010;9(6):10.1016/S1474-4422(10)70124-1.
PMCID: PMC3817610  PMID: 20494320
20.  Alcohol consumption in 0.5 million people from 10 diverse regions of China: prevalence, patterns and socio-demographic and health-related correlates 
Millwood, Iona Y | Li, Liming | Smith, Margaret | Guo, Yu | Yang, Ling | Bian, Zheng | Lewington, Sarah | Whitlock, Gary | Sherliker, Paul | Collins, Rory | Chen, Junshi | Peto, Richard | Wang, Hongmei | Xu, Jiujiu | He, Jian | Yu, Min | Liu, Huilin | Chen, Zhengming | Li, Liming | Chen, Zhengming | Chen, Junshi | Collins, Rory | Wu, Fan | Peto, Richard | Chen, Zhengming | Lancaster, Garry | Yang, Xiaoming | Williams, Alex | Smith, Margaret | Yang, Ling | Chang, Yumei | Millwood, Iona | Chen, Yiping | Zhang, Qiuli | Lewington, Sarah | Whitlock, Gary | Guo, Yu | Zhao, Guoqing | Bian, Zheng | Wu, Lixue | Hou, Can | Pang, Zengchang | Wang, Shaojie | Zhang, Yun | Zhang, Kui | Liu, Silu | Zhao, Zhonghou | Liu, Shumei | Pang, Zhigang | Feng, Weijia | Wu, Shuling | Yang, Liqiu | Han, Huili | He, Hui | Pan, Xianhai | Wang, Shanqing | Wang, Hongmei | Hao, Xinhua | Chen, Chunxing | Lin, Shuxiong | Hu, Xiaoshu | Zhou, Minghao | Wu, Ming | Wang, Yeyuan | Hu, Yihe | Ma, Liangcai | Zhou, Renxian | Xu, Guanqun | Dong, Baiqing | Chen, Naying | Huang, Ying | Li, Mingqiang | Meng, Jinhuai | Gan, Zhigao | Xu, Jiujiu | Liu, Yun | Wu, Xianping | Gao, Yali | Zhang, Ningmei | Luo, Guojin | Que, Xiangsan | Chen, Xiaofang | Ge, Pengfei | He, Jian | Ren, Xiaolan | Zhang, Hui | Mao, Enke | Li, Guanzhong | Li, Zhongxiao | He, Jun | Liu, Guohua | Zhu, Baoyu | Zhou, Gang | Feng, Shixian | Gao, Yulian | He, Tianyou | Jiang, Li | Qin, Jianhua | Sun, Huarong | Liu, Liqun | Yu, Min | Chen, Yaping | Hu, Zhixiang | Hu, Jianjin | Qian, Yijian | Wu, Zhiying | Chen, Lingli | Liu, Wen | Li, Guangchun | Liu, Huilin | Long, Xiangquan | Xiong, Youping | Tan, Zhongwen | Xie, Xuqiu | Peng, Yunfang
Background Drinking alcohol has a long tradition in Chinese culture. However, data on the prevalence and patterns of alcohol consumption in China, and its main correlates, are limited.
Methods During 2004–08 the China Kadoorie Biobank recruited 512 891 men and women aged 30–79 years from 10 urban and rural areas of China. Detailed information on alcohol consumption was collected using a standardized questionnaire, and related to socio-demographic, physical and behavioural characteristics in men and women separately.
Results Overall, 76% of men and 36% of women reported drinking some alcohol during the past 12 months, with 33% of men and 2% of women drinking at least weekly; the prevalence of weekly drinking in men varied from 7% to 51% across the 10 study areas. Mean consumption was 286 g/week and was higher in those with less education. Most weekly drinkers habitually drank spirits, although this varied by area, and beer consumption was highest among younger drinkers; 37% of male weekly drinkers (12% of all men) reported weekly heavy drinking episodes, with the prevalence highest in younger men. Drinking alcohol was positively correlated with regular smoking, blood pressure and heart rate. Among male weekly drinkers, each 20 g/day alcohol consumed was associated with 2 mmHg higher systolic blood pressure. Potential indicators of problem drinking were reported by 24% of male weekly drinkers.
Conclusion The prevalence and patterns of drinking in China differ greatly by age, sex and geographical region. Alcohol consumption is associated with a number of unfavourable health behaviours and characteristics.
PMCID: PMC3733702  PMID: 23918852
Alcohol; drinking; cohort study; descriptive analysis; China
21.  Augmented BMPRIA-Mediated BMP Signaling in Cranial Neural Crest Lineage Leads to Cleft Palate Formation and Delayed Tooth Differentiation 
PLoS ONE  2013;8(6):e66107.
The importance of BMP receptor Ia (BMPRIa) mediated signaling in the development of craniofacial organs, including the tooth and palate, has been well illuminated in several mouse models of loss of function, and by its mutations associated with juvenile polyposis syndrome and facial defects in humans. In this study, we took a gain-of-function approach to further address the role of BMPR-IA-mediated signaling in the mesenchymal compartment during tooth and palate development. We generated transgenic mice expressing a constitutively active form of BmprIa (caBmprIa) in cranial neural crest (CNC) cells that contributes to the dental and palatal mesenchyme. Mice bearing enhanced BMPRIa-mediated signaling in CNC cells exhibit complete cleft palate and delayed odontogenic differentiation. We showed that the cleft palate defect in the transgenic animals is attributed to an altered cell proliferation rate in the anterior palatal mesenchyme and to the delayed palatal elevation in the posterior portion associated with ectopic cartilage formation. Despite enhanced activity of BMP signaling in the dental mesenchyme, tooth development and patterning in transgenic mice appeared normal except delayed odontogenic differentiation. These data support the hypothesis that a finely tuned level of BMPRIa-mediated signaling is essential for normal palate and tooth development.
PMCID: PMC3680418  PMID: 23776616
22.  Expression of SHH signaling molecules in the developing human primary dentition 
Our current knowledge on tooth development derives primarily from studies in mice. Very little is known about gene expression and function during human odontogenesis. Sonic Hedgehog (SHH) signaling has been demonstrated to play crucial roles in the development of multiple organs in mice, including the tooth. However, if SHH signaling molecules are expressed and function in the developing human embryonic tooth remain unknown.
We conducted microarray assay to reveal the expression profile of SHH signaling pathway molecules. We then used in situ hybridization to validate and reveal spatial and temporal expression patterns of a number of selected molecules, including SHH, PTC1, SMO, GLI1, GLI2, and GLI3, in the developing human embryonic tooth germs, and compared them with that in mice. We found that all these genes exhibit similar but slightly distinct expression patterns in the human and mouse tooth germ at the cap and bell stages.
Our results demonstrate the operation of active SHH signaling in the developing human tooth and suggest a conserved function of SHH signaling pathway during human odontogenesis.
PMCID: PMC3639830  PMID: 23566240
Deciduous tooth; Tooth development; Gene expression; SHH; PTC; SMO; GLI
23.  Tissue interaction is required for glenoid fossa development during temporomandibular joint formation 
The mammalian temporomandibular joint (TMJ) develops from two distinct mesenchymal condensations that grow towards each other and ossify through different mechanisms, with the glenoid fossa undergoing intramembranous ossification while the condyle being endochondral in origin. In this study, we used various genetically modified mouse models to investigate tissue interaction between the condyle and glenoid fossa during TMJ formation in mice. We report that either absence or dislocation of the condyle results in an arrested glenoid fossa development. In both cases, glenoid fossa development was initiated, but failed to sustain, and became regressed subsequently. However, condyle development appears to be independent upon the presence of the forming glenoid fossa. In addition, we show that substitution of condyle by Meckel’s cartilage is able to sustain glenoid fossa development. These observations suggest that proper signals from the developing condyle or Meckel’s cartilage are required to sustain the glenoid fossa development.
PMCID: PMC3197963  PMID: 21953591
TMJ formation; glenoid fossa development; condyle; tissue interaction; Sox9
24.  Epilogue: Lessons from the CONVERGE study of major depressive disorder in China 
Journal of Affective Disorders  2012;140-334(1):1-5.
This review summarizes the first clinical reports from the CONVERGE consortium: China, Oxford and VCU Experimental Research on Genetic Epidemiology. CONVERGE sets out to investigate the nature and mode of action of the genetic and environmental risk factors for major depressive disorder (MDD). CONVERGE aims to collect 6000 cases of recurrent MDD and 6000 controls. The consortium includes hospitals in 30 cities, all with populations exceeding 5 million, and has collected over 2000 cases and controls. High quality phenotype data on MDD collected in China is now available to determine the source and nature of this highly heterogeneous condition. Analyses reported in a series of papers indicate that the clinical features and risk factors of MDD are sufficiently similar to those in the West that we can confidently predict that the results of subsequent analyses will be widely applicable.
PMCID: PMC3387371  PMID: 21955396
Major depressive disorder; China; Co-morbidity; Anxiety
25.  Ectopic expression of Nkx2.5 suppresses the formation of the sinoatrial node in mice 
Developmental biology  2011;356(2):359-369.
The sinoatrial node (SAN), functionally known as the pacemaker, regulates the cardiac rhythm or heart beat. Several genes are expressed in the developing SAN and form a genetic network regulating the fate of the SAN cells. The short stature homeobox gene Shox2 is an important player in the SAN genetic network by regulating the expression of different cardiac conduction molecular markers including the early cardiac differentiation marker Nkx2.5. Here we report that the expression patterns of Shox2 and Nkx2.5 are mutually exclusive from the earliest stages of the venous pole and the SAN formation. We show that tissue specific ectopic expression of Shox2 in the developing mouse heart downregulates the expression of Nkx2.5 and causes cardiac malformations; however, it is not sufficient to induce a SAN cell fate switch in the working myocardium. On the other hand, tissue specific overexpression of Nkx2.5 in the heart leads to severe hypoplasia of the SAN and the venous valves, dis-regulation of the SAN genetic network, and change of the SAN cell fate into working myocardium, and causes embryonic lethality, recapitulating the phenotypes including bradycardia observed in Shox2−/− mutants. These results indicate that Nkx2.5 activity is detrimental to the normal formation of the SAN. Taken together, our results demonstrate that Shox2 downregulation of Nkx2.5 is essential for the proper development of the SAN and that Shox2 functions to shield the SAN from becoming working myocardium by acting upstream of Nkx2.5.
PMCID: PMC3143305  PMID: 21640717
Shox2; Nkx2.5; sinoatrial node; pacemaker; heart development

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