Activation of transforming growth factor-beta (TGF-beta) and activin receptors leads to phosphorylation of Sma- and Mad-related protein 2 (Smad2) and Smad3, which function as transcription factors to regulate gene expression. Smad7 is a regulatory protein which is able to inhibit TGF-beta and activin signalling in a negative-feedback loop, mediated by a direct regulation by Smad3 and Smad4 via a Smad-binding element (SBE) in the Smad7 promoter. Interestingly, we found that the Smad7 promoter was also regulated by nuclear factor kappaB (NF-kappaB), a transcription factor which plays an important role in inflammation and the immune response. Expression of NF-kappaB p65 subunit was able to inhibit the Smad7 promoter activity, and this inhibition could be reversed by co-expression of IkappaB, an inhibitor of NF-kappaB. In addition, the inhibitory activity of p65 was observed in a minimal promoter that contained only the Smad7 SBE and a TATA box, without any consensus NF-kappaB binding site. This inhibitory effect appeared to be common to other TGF-beta- and activin-responsive promoters, since p65 also inhibited the forkhead-activin-signal-transducer-2-mediated activation of a Xenopus Mix.2 promoter, as well as the Smad3-mediated activation of 3TP-lux which contains PMA-responsive elements and a plasminogen-activator-inhibitor-1 promoter. Activation of endogenous NF-kappaB by tumour necrosis factor-alpha (TNF-alpha) was also able to inhibit the Smad7 promoter in human embryonic kidney 293 cells. In human hepatoma HepG2 cells, TNF-alpha was able to inhibit TGF-beta- and activin-mediated transcriptional activation. Furthermore, overexpression of the transcription co-activator p300 could abrogate the inhibitory effect of NF-kappaB on the Smad7 promoter. Taken together, these data have indicated a novel mode of crosstalk between the Smad and the NF-kappaB signalling cascades at the transcriptional level by competing for a limiting pool of transcription co-activators.
Key pointsr Women with polycystic ovary syndrome (PCOS) commonly suffer from miscarriage, but the underlying mechanisms remain unknown.r Herein, pregnant rats chronically treated with 5α-dihydrotestosterone (DHT) and insulin exhibited hyperandrogenism and insulin resistance, as well as increased fetal loss, and these features are strikingly similar to those observed in pregnant PCOS patients.r Fetal loss in our DHT+insulin-treated pregnant rats was associated with mitochondrial dysfunction, disturbed superoxide dismutase 1 and Keap1/Nrf2 antioxidant responses, over-production of reactive oxygen species (ROS) and impaired formation of the placenta.r Chronic treatment of pregnant rats with DHT or insulin alone indicated that DHT triggered many of the molecular pathways leading to placental abnormalities and fetal loss, whereas insulin often exerted distinct effects on placental gene expression compared to co-treatment with DHT and insulin.r Treatment of DHT+insulin-treated pregnant rats with the antioxidant N-acetylcysteine improved fetal survival but was deleterious in normal pregnant rats.r Our results provide insight into the fetal loss associated with hyperandrogenism and insulin resistance in women and suggest that physiological levels of ROS are required for normal placental formation and fetal survival during pregnancy.Yuehui Zhang is a professor and chief physician in the . She carried out postdoctoral research training in reproductive endocrinology at the University of Gothenburg, Sweden and obstetrics and gynaecology at the University of Pennsylvania, USA. Her research aims are to uncover the cellular and molecular mechanisms in aetiologies of polycystic ovary syndrome (PCOS) and other gynaecological diseases, as well as to develop an effective treatment for PCOS patients.Abstract Women with polycystic ovary syndrome (PCOS) commonly suffer from miscarriage, but the underlying mechanism of PCOS-induced fetal loss during pregnancy remains obscure and specific therapies are lacking. We used pregnant rats treated with 5α-dihydrotestosterone (DHT) and insulin to investigate the impact of hyperandrogenism and insulin resistance on fetal survival and to determine the molecular link between PCOS conditions and placental dysfunction during pregnancy. Our study shows that pregnant rats chronically treated with a combination of DHT and insulin exhibited endocrine aberrations such as hyperandrogenism and insulin resistance that are strikingly similar to those in pregnant PCOS patients. Of pathophysiological significance, DHT+insulin-treated pregnant rats had greater fetal loss and subsequently decreased litter sizes compared to normal pregnant rats. This negative effect was accompanied by impaired trophoblast differentiation, increased glycogen accumulation, and decreased angiogenesis in the placenta. Mechanistically, we report that over-production of reactive oxygen species (ROS) in the placenta, mitochondrial dysfunction, and disturbed superoxide dismutase 1 (SOD1) and Keap1/Nrf2 antioxidant responses constitute im...
ObjectiveEchinococcosis is a major parasitic zoonosis of public health importance in western China. In 2004, the Chinese Ministry of Health estimated that 380,000 people had the disease in the region. The Qinghai-Tibet Plateau is highly co-endemic with both alveolar echinococcosis (AE) and cystic echinococcosis (CE). In the past years, the Chinese government has been increasing the financial support to control the diseases in this region. Therefore, it is very important to identify the significant risk factors of the diseases by reviewing studies done in the region in the past decade to help policymakers design appropriate control strategies.ReviewSelection criteria for which literature to review were firstly defined. Medline, CNKI (China National Knowledge Infrastructure), and Google Scholar were systematically searched for literature published between January 2000 and July 2011. Significant risk factors found by single factor and/or multiple factors analysis were listed, counted, and summarized. Literature was examined to check the comparability of the data; age and sex specific prevalence with same data structures were merged and used for further analysis.A variety of assumed social, economical, behavioral, and ecological risk factors were studied on the Plateau. Those most at risk were Tibetan herdsmen, the old and female in particular. By analyzing merged comparable data, it was found that females had a significant higher prevalence, and a positive linearity relationship existed between echinococcosis prevalence and increasing age. In terms of behavioral risk factors, playing with dogs was mostly correlated with CE and/or AE prevalence. In terms of hygiene, employing ground water as the drinking water source was significantly correlated with CE and AE prevalence. For definitive hosts, dog related factors were most frequently identified with prevalence of CE or/and AE; fox was a potential risk factor for AE prevalence only. Overgrazing and deforestation were significant for AE prevalence only.ConclusionTibetan herdsmen communities were at the highest risk of echinococcosis prevalence and should be the focus of echinococcosis control. Deworming both owned and stray dogs should be a major measure for controlling echinococcosis; treatment of wild definitive hosts should also be considered for AE endemic areas. Health education activities should be in concert with the local people’s education backgrounds and languages in order to be able to improve behaviors. Further researches are needed to clarify the importance of wild hosts for AE/CE prevalence, the extent and range of the impacts of ecologic changes (overgrazing and deforestation) on the AE prevalence, and risk factors in Tibet.
These data illustrate a paradox in which the incidence of disease is greater for males, but the severity of disease outcome is worse for females. Several behavioral, societal, and biological factors are hypothesized to be involved.
Gestational diabetes mellitus (GDM) accounts for approximately 7% of all pregnancies in the United States and China. 1,2 Women with GDM are at an increased risk of adverse pregnancy outcomes, such as giving birth to babies with greater birth weight and primary cesarean delivery. 3 Maternal GDM also exerts a long-term influence on the offspring, which was named "metabolic imprinting" by some researchers. 4 Previous studies indicated that offspring of mothers with GDM were predisposed to metabolic syndrome and its components. 4-12 However, the results about the association between maternal GDM and offspring's risk for hypertension were controversial. Several studies have indicated that offspring of mothers with GDM had higher mean values of systolic blood pressure (SBP) or diastolic blood pressure (DBP) than children of mothers without GDM mothers. 11-14 Other studies reported no difference in the levels of SBP and DBP between the 2 groups. 7,8 However, most of these previous studies are largely limited by small samples sizes (20-130 GDM cases) and different diagnosis methods of maternal GDM, and whether maternal GDM means a higher risk of pediatric hypertension remains uncertain. Moreover, the extent to which childhood hypertension associated with maternal GDM could be explained by other confounders remains unclear. To elucidate these issues, we compared childhood blood pressure levels and the risk of hypertension
In recent years, as an increasing number of neuronal autoantibodies have been detected and used for clinical diagnosis, clinicians have become more aware of autoimmune encephalitis, causing its reported incidence to trend upward over several years. To date, however, there has been no large-scale epidemiological survey of autoimmune encephalitis in adults and children, and its epidemiological characteristics remain unclear. Six main types of antibodies are detected and used to diagnose autoimmune encephalitis in Chongqing, Southwestern China: anti-NMDA receptor antibody, anti-GABAB receptor antibody, anti-LGI1 antibody, anti-CASPR2 antibody, anti-AMPA1 receptor antibody, and anti-AMPA2 receptor antibody. From January 2012 to February 2018, 189 patients at six general hospitals in Chongqing were diagnosed with autoimmune encephalitis and were positive for neuronal autoantibodies. In this report, the epidemic situation and the antibody distribution among these patients are analyzed and described in detail. The differences in disease severity among different ages and between the sexes are evaluated, and the correlation between antibody titer and disease severity is also assessed.
Renal dysfunction predicts all-cause mortality in general population. However, the prevalence of renal insufficiency and its relationship with mortality in cancer patients are unclear.We retrospectively studied 9465 patients with newly diagnosed cancer from January 2010 to December 2010. Renal insufficiency was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 using the Chronic Kidney Disease Epidemiology Collaboration equation. The hazard ratio (HR) of all-cause mortality associated with baseline eGFR was assessed by Cox regression.Three thousand sixty-nine patients (32.4%) exhibited eGFR <90 mL/min/1.73 m2 and 3% had abnormal serum creatinine levels at the time of diagnosis. Over a median follow-up of 40.5 months, 2705 patients (28.6%) died. Compared with the reference group (eGFR ≥ 60 mL/min/1.73 m2), an elevated all-cause mortality was observed among patients with eGFR < 60 mL/min/1.73 m2 stratified by cancer stage in the entire cohort, the corresponding hazard ratios were 1.87 (95% CI, 1.41–2.47) and 1.28 (95% CI, 1.01–1.62) for stage I to III and stage IV, respectively. However, this relationship was not observed after multivariate adjustment. Subgroup analysis found that eGFR < 60 mL/min/1.73 m2 independently predicted death among patients with hematologic (adjusted HR 2.93, 95% CI [1.36–6.31]) and gynecological cancer (adjusted HR 2.82, 95% CI [1.19–6.70]), but not in those with other cancer. Five hundred fifty-seven patients (6%) had proteinuria. When controlled for potential confounding factors, proteinuria was a risk factor for all-cause mortality among patients in the entire cohort, regardless of cancer stage and eGFR values. When patients were categorized by specific cancer type, the risk of all-cause death was only significant in patients with digestive system cancer (adjusted HR, 1.85 [1.48–2.32]).The prevalence of renal dysfunction was common in patients with newly diagnosed cancer. Patients with eGFR < 60 mL/min/1.73 m2 or proteinuria were associated with increased risk for all-cause mortality, this relation depended on cancer site.
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