The Risk of Cervical Cancer in Women Among Han, Bai, Dai and Hani Ethnic Minorities in Yunnan Province of China.

Background: Research on the risk factors for cervical cancer in Yunnan Province's four characteristic ethnic groups (Han, Bai, Dai, and Hani) is lacking. Objective: To study the risk factors of cervical cancer in four ethnic women in Yunnan Province, and to provide evidence for its prevention. Methods: The cervical cancer patients of Han, Bai, Dai and Hani ethnic groups in Yunnan Province who were first diagnosed in the Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center) from January 2011 to December 2020 were selected as the research objects. The 1:1 matched case-control study method was used, and single factor and conditional logistic regression were used for statistical analysis. Results: HPV types 16, 18 and 58 are mostly related with cervical cancer, the younger the age of the last pregnancy, the more times of pregnancy, childbirth and abortion, especially the younger the first marriage age of Bai and Dai, are the risk factors of cervical cancer; the infection of genital tract bacteria, mycoplasma and chlamydia is closely related to the incidence of cervical cancer in four ethnicities. Multifactorial analysis showed that demographic characteristics and environment/behavior were not included in the influencing factors of cervical cancer; among Han, Bai, Dai and Hani ethnic minorities, contraception (OR=0.29, OR=0.03, OR=0.09, OR=0.16, P<0.05) was positive factor, HPV infection (OR=64.77, OR=128.71, OR=71.89, OR=40.07, P<0.01) was a causative factor of cervical cancer. Conclusion: Risk of high parity with cervical cancer could be due to a complex interplay of factors, it is very important to formulate prevention strategies and measures in line with the cervical cancer of Han, Bai, Dai and Hani ethnic groups women in Yunnan Province.

Endogenous Adenosine 5'-Monophosphate, But Not Acetylcholine or Histamine, is Associated with Asthma Control, Quality of Life, and Exacerbations.

OBJECTIVE: Endogenous adenosine 5'-monophosphate (AMP), acetylcholine (ACh), and histamine (HA) are known to be important in bronchial contraction, but their clinical relevance to asthma is poorly understood. We aimed to quantify endogenous AMP, ACh, and HA in induced sputum samples and explore their relationships with asthma control and exacerbations. METHODS: 20 healthy subjects and 112 asthmatics underwent clinical assessment, sputum induction, and blood sampling. The level of asthma control was determined by the asthma control test (ACT) questionnaire. Asthma exacerbation was evaluated according to the criteria of the American Thoracic Society/European Respiratory Society. Levels of AMP, ACh, and HA in sputum were measured by liquid chromatography coupled to tandem mass spectrometry. IL-ß, IL-4, IL-5, IL-6, IL-8, IL-13, IL-17A, TNF-α, IFN-γ, and macrophage-derived chemokine (MDC) were also measured. RESULTS: Compared to healthy controls, asthmatics had higher levels of HA, lower levels of ACh, and similar levels of AMP in induced sputum samples. Compared to controlled asthma (n = 54), uncontrolled asthma (n = 58) showed higher AMP levels (P = 0.002), but similar HA and ACh levels. AMP was negatively correlated with ACT scores (r = - 0.348) and asthma quality of life questionnaire scores (r = - 0.188) and positively correlated with blood monocytes percentage (r = 0.195), sputum MDC (r = 0.214), and IL-6 levels (r = 0.196). Furthermore, AMP was associated with an increased risk of exacerbations in the preceding year. CONCLUSION: Endogenous AMP, but not ACh or HA, was associated with asthma control, quality of life, and exacerbations in the previous year, which indicates that AMP could be a clinically useful biomarker of asthma.

Treatable Traits in Elderly Asthmatics from the Australasian Severe Asthma Network: A Prospective Cohort Study.

BACKGROUND: Data on treatable traits (TTs) in different populations are limited. OBJECTIVE: To assess TTs in elderly patients with asthma and compare them to younger patients, to evaluate the association of TTs with future exacerbations, and to develop an exacerbation prediction model. METHODS: We consecutively recruited 521 participants at West China Hospital, Sichuan University based on the Australasian Severe Asthma Network, classified as elderly (n = 62) and nonelderly (n = 459). Participants underwent a multidimensional assessment to characterize the TTs and were then followed up for 12 months. TTs and their relationship with future exacerbations were described. Based on the TTs and asthma control levels, an exacerbation prediction model was developed, and the overall performance was externally validated in an independent cohort. RESULTS: A total of 38 TTs were assessed. Elderly patients with asthma had more chronic metabolic diseases, fixed airflow limitation, emphysema, and neutrophilic inflammation, whereas nonelderly patients with asthma exhibited more allergic characteristics and psychiatric diseases. Nine traits were associated with increased future exacerbations, of which exacerbation prone, upper respiratory infection-induced asthma attack, cardiovascular disease, diabetes, and depression were the strongest. A model including exacerbation prone, psychiatric disease, cardiovascular disease, upper respiratory infection-induced asthma attack, noneosinophilic inflammation, cachexia, food allergy, and asthma control was developed to predict exacerbation risk and showed good performance. CONCLUSIONS: TTs can be systematically assessed in elderly patients with asthma, some of which are associated with future exacerbations, proving their clinical utility of evaluating them. A model based on TTs can be used to predict exacerbation risk in people with asthma.

Growth differentiation factor-15 slows the growth of murine prostate cancer by stimulating tumor immunity.

Growth Differentiation Factor-15 (GDF15) is a divergent TGF-beta superfamily cytokine that is overexpressed by most cancers and is induced by anticancer therapy. Transgenic and induced animal models suggest that it protects from cancer development but the mechanisms are uncertain. We investigated the role of immunity in GDF15 induced reduction in prostate cancer (PCa) growth. The C57BL/6 transgenic TRAMP prostate cancer prone mice were bred with mice that were immunodeficient and/or systemically overexpressed GDF15. We developed a novel orthotopic TRAMP PCa model in which primary TRAMP tumor cells were implanted into prostates of mice to reduce the study time. These mice were administered recombinant mouse GDF15, antibody to CD8, PD1 or their respective controls. We found that GDF15 induced protection from tumor growth was reversed by lack of adaptive immunity. Flow cytometric evaluation of lymphocytes within these orthotopic tumors showed that GDF15 overexpression was associated with increased CD8 T cell numbers and an increased number and proportion of recently activated CD8+CD11c+ T cells and a reduced proportion of "exhausted" CD8+PD1+ T cells. Further, depletion of CD8 T cells in tumor bearing mice abolished the GDF15 induced protection from tumor growth. Infusion of GDF15 into mice bearing orthotopic TRAMP tumor, substantially reduced tumor growth that was further reduced by concurrent PD1 antibody administration. GDF15 overexpression or recombinant protein protects from TRAMP tumor growth by modulating CD8 T cell mediated antitumor immunity and augments the positive effects of anti-PD1 blockers.

A case report of Turner syndrome associated with fetal nuchal cystic hygroma and bilateral syndactyly of the hands and feet.

BACKGROUND: Turner syndrome (45,X), accounts for 1-2% of conceptions which typically miscarry early in the first trimester. Cases detected prenatally often present with cystic hygroma, which is an ultrasound marker for aneuploidy generally, but Turner syndrome particularly. In this study, we report a second trimester intrauterine fetal demise (IUFD), complicated by a marked cystic hygroma and bilateral syndactyly of the fingers and toes. CASE PRESENTATION: A 25-year-old woman presented for her first prenatal visit at 22-week gestation with IUFD. Color Doppler ultrasound revealed a septated nuchal lymphatic hygroma and hydrops fetalis, characterized by edema of the whole body, substantial pleural effusion and abdominal fluid. Pregnancy was further complicated by oligohydramnios. Following labor induction, a stillborn female baby was delivered at 22 weeks gestation. Autopsy confirmed the presence of huge nuchal cystic hygroma (10 cm × 10 cm × 6 cm) and generalized edema. Bilateral, partial syndactyly involving digits 2-5 of the fingers and toes were also observed. Chromosomal analysis revealed a 45,X karyotype. CONCLUSIONS: We investigated an unusual case of severe septated nuchal cystic hygroma associated with bilateral syndactyly of the fingers and toes in a stillborn infant with Turner syndrome. Although cystic hygroma has been frequently reported in 45,X the severity is marked in this case. In addition, syndactyly is not a typical complication of Turner syndrome. This case emphasizes the importance of early ultrasound in pregnancy.

GDF15 mediates adiposity resistance through actions on GFRAL neurons in the hindbrain AP/NTS.

BACKGROUND: Elevated circulating levels of the divergent transforming growth factor-beta (TGFb) family cytokine, growth differentiation factor 15 (GDF15), acting through its CNS receptor, glial-derived neurotrophic factor receptor alpha-like (GFRAL), can cause anorexia and weight loss leading to anorexia/cachexia syndrome of cancer and other diseases. Preclinical studies suggest that administration of drugs based on recombinant GDF15 might be used to treat severe obesity. However, the role of the GDF15-GFRAL pathway in the physiological regulation of body weight and metabolism is unclear. The critical site of action of GFRAL in the CNS has also not been proven beyond doubt. To investigate these two aspects, we have inhibited the actions of GDF15 in mice started on high-fat diet (HFD). METHODS: The actions of GDF15 were inhibited using two methods: (1) Groups of 8 mice under HFD had their endogenous GDF15 neutralised by monoclonal antibody treatment, (2) Groups of 15 mice received AAV-shRNA to knockdown GFRAL at its hypothesised major sites of action, the hindbrain area postrema (AP) and the nucleus of the solitary tract (NTS). Metabolic measurements were determined during both experiments. CONCLUSIONS: Treating mice with monoclonal antibody to GDF15 shortly after commencing HFD results in more rapid gain of body weight, adiposity and hepatic lipid deposition than the control groups. This is accompanied by reduced glucose and insulin tolerance and greater expression of pro-inflammatory cytokines in adipose tissue. Localised AP and NTS shRNA-GFRAL knockdown in mice commencing HFD similarly caused an increase in body weight and adiposity. This effect was in proportion to the effectiveness of GFRAL knockdown, indicated by quantitative analysis of hindbrain GFRAL staining. We conclude that the GDF15-GFRAL axis plays an important role in resistance to obesity in HFD-fed mice and that the major site of action of GDF15 in the CNS is GFRAL-expressing neurons in the AP and NTS.

Depressive symptom-associated IL-1ß and TNF-α release correlates with impaired bronchodilator response and neutrophilic airway inflammation in asthma.

BACKGROUND: Depressive symptoms worsen asthma outcomes; however, the mechanism remains largely unexplored. OBJECTIVE: This study aimed to determine whether depressive symptom-associated immune inflammation correlates with impaired bronchodilator response (BDR) and airway inflammatory phenotypes. METHODS: Eligible adults with asthma (n = 198) underwent clinical assessment, sputum induction and blood sampling. Depressive symptoms were defined by scores on the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D). Pre- and post-bronchodilator spirometry was performed for BDR. Airway inflammatory phenotypes were defined by sputum cell counts. CRP, IL-1ß, IL-5, IL-6, IL-8, TNF-α, IFN-γ, CCL17 and CCL22 in serum and sputum were detected. RESULTS: Compared with the non-depressive group (n = 174), the depressive group (n = 24) exhibited impaired BDR (P = 0.032) and increased sputum neutrophils (P = 0.023), which correlated with the HADS-D scores (P = 0.027 and P = 0.029). Levels of IL-1ß, TNF-α and IFN-γ in the serum and those of IL-1ß and IFN-γ in the sputum were elevated in the depressive group compared to those in the non-depressive group (all P < 0.05). Multiple regression models indicated that TNF-α in the sputum and IL-1ß, IL-6 and IFN-γ in both the serum and sputum were inversely associated with BDR; TNF-α in the sputum and IL-1ß in both the serum and sputum were positively correlated with sputum neutrophils. Mediation analyses revealed that IL-1ß and TNF-α in the sputum and IL-1ß in both the serum and sputum mediate the correlations of the HADS-D scores with BDR and sputum neutrophils, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Asthma patients with depressive symptoms present worse asthma control, which is most likely explained by impaired BDR and neutrophilic airway inflammation. IL-1ß and TNF-α, which are two key pro-inflammatory cytokines that mediate the correlation of depressive symptoms with impaired BDR and neutrophilic airway inflammation, may serve as targeted biomarkers in the neuropsychological phenotype of asthma; however, this result needs to be further validated.

Obesity-Associated Metabolic Signatures Correlate to Clinical and Inflammatory Profiles of Asthma: A Pilot Study.

PURPOSE: Obesity is associated with metabolic dysregulation, but the underlying metabolic signatures involving clinical and inflammatory profiles of obese asthma are largely unexplored. We aimed at identifying the metabolic signatures of obese asthma. METHODS: Eligible subjects with obese (n = 11) and lean (n = 22) asthma underwent body composition and clinical assessment, sputum induction, and blood sampling. Sputum supernatant was assessed for interleukin (IL)-1ß, -4, -5, -6, -13, and tumor necrosis factor (TNF)-α, and serum was detected for leptin, adiponectin and C-reactive protein. Untargeted gas chromatography time-of-flight mass spectrometry (GC-TOF-MS)-based metabolic profiles in sputum, serum and peripheral blood monocular cells (PBMCs) were analyzed by orthogonal projections to latent structures-discriminate analysis (OPLS-DA) and pathway topology enrichment analysis. The differential metabolites were further validated by correlation analysis with body composition, and clinical and inflammatory profiles. RESULTS: Body composition, asthma control, and the levels of IL-1ß, -4, -13, leptin and adiponectin in obese asthmatics were significantly different from those in lean asthmatics. OPLS-DA analysis revealed 28 differential metabolites that distinguished obese from lean asthmatic subjects. The validation analysis identified 18 potential metabolic signatures (11 in sputum, 4 in serum and 2 in PBMCs) of obese asthmatics. Pathway topology enrichment analysis revealed that cyanoamino acid metabolism, caffeine metabolism, alanine, aspartate and glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, pentose phosphate pathway in sputum, and glyoxylate and dicarboxylate metabolism, glycerolipid metabolism and pentose phosphate pathway in serum are suggested to be significant pathways related to obese asthma. CONCLUSIONS: GC-TOF-MS-based metabolomics indicates obese asthma is characterized by a metabolic profile different from lean asthma. The potential metabolic signatures indicated novel immune-metabolic mechanisms in obese asthma with providing more phenotypic and therapeutic implications, which needs further replication and validation.

Recent advances on the role of long non-coding RNA H19 in regulating mammalian muscle growth and development.

As one of the first identified long non-coding RNAs (lncRNAs), H19 plays a wide range of roles in vivo, including not only as a tumor suppressor and oncogene involved in disease process, but also as a regulator of growth and development of multiple tissues in mammalian embryos. The function of H19 in muscles (both skeletal and cardiac muscle) draws widespread attention due to the following two reasons. On one hand, H19 promotes myogenic differentiation and myogenesis of skeletal muscle satellite cells (SMSCs) via regulating Igf2 in cis. On the other hand, H19 also modulates the target genes in trans, including sponging let-7, miR-106 or miR-29 to mediate myocyte glucose uptake, cardiomyocyte proliferation and tendon repair, as well as promote embryonic development and muscle regeneration through binding to MBD1 as a chromatin modifier. In this review, we summarize the role of H19 in mammalian muscles, which will provide a reference for further research to unveil the molecular mechanism of muscle growth and development.

Identification and validation of asthma phenotypes in Chinese population using cluster analysis.

BACKGROUND: Asthma is a heterogeneous airway disease, so it is crucial to clearly identify clinical phenotypes to achieve better asthma management. OBJECTIVE: To identify and prospectively validate asthma clusters in a Chinese population. METHODS: Two hundred eighty-four patients were consecutively recruited and 18 sociodemographic and clinical variables were collected. Hierarchical cluster analysis was performed by the Ward method followed by k-means cluster analysis. Then, a prospective 12-month cohort study was used to validate the identified clusters. RESULTS: Five clusters were successfully identified. Clusters 1 (n = 71) and 3 (n = 81) were mild asthma phenotypes with slight airway obstruction and low exacerbation risk, but with a sex differential. Cluster 2 (n = 65) described an "allergic" phenotype, cluster 4 (n = 33) featured a "fixed airflow limitation" phenotype with smoking, and cluster 5 (n = 34) was a "low socioeconomic status" phenotype. Patients in clusters 2, 4, and 5 had distinctly lower socioeconomic status and more psychological symptoms. Cluster 2 had a significantly increased risk of exacerbations (risk ratio [RR] 1.13, 95% confidence interval [CI] 1.03-1.25), unplanned visits for asthma (RR 1.98, 95% CI 1.07-3.66), and emergency visits for asthma (RR 7.17, 95% CI 1.26-40.80). Cluster 4 had an increased risk of unplanned visits (RR 2.22, 95% CI 1.02-4.81), and cluster 5 had increased emergency visits (RR 12.72, 95% CI 1.95-69.78). Kaplan-Meier analysis confirmed that cluster grouping was predictive of time to the first asthma exacerbation, unplanned visit, emergency visit, and hospital admission (P < .0001 for all comparisons). CONCLUSION: We identified 3 clinical clusters as "allergic asthma," "fixed airflow limitation," and "low socioeconomic status" phenotypes that are at high risk of severe asthma exacerbations and that have management implications for clinical practice in developing countries.

Bone Age and Serum Osteocalcin Levels in Children With Obstructive Sleep Apnea Hypopnea Syndrome Before and After Adenotonsillectomy.

Our aim was to study the changes in bone age and serum osteocalcin levels before and after adenotonsillectomy (AT) in children with obstructive sleep apnea hypopnea syndrome (OSAHS). A total of 58 OSAHS children (37 males and 21 females) with the mean age of 6.68 ± 1.11 years were enrolled and assessed by x-ray-based bone age estimation and enzyme-linked immunosorbent assay-based measurement of serum osteocalcin levels, before surgery and 6 months after AT. SPSS 19.0 software was used for statistical analysis. Our results revealed that bone age and serum osteocalcin levels in OSAHS patients were significantly lower than normal controls before AT (P < 0.05). Within 6 months after surgery, the bone age and the serum osteocalcin levels were significantly elevated in OSAHS patients (P < 0.05), compared with those before surgery. Serum osteocalcin levels and bone age are negatively correlated with apnea-hypopnea index, oxygen desaturation index, the percentage of the total recorded time spent below 90% oxygen saturation, and Epworth sleepiness scale scores (all P < 0.05). Our findings suggested that bone age and serum osteocalcin levels may be correlated with the development of OSAHS in children. AT may improve bone age and serum osteocalcin levels in OSAHS children.

Band structure of graphene modulated by Ti or N dopants and applications in gas sensoring.

The exploration of novel sensors for NO2 detection is particularly important in material and environmental sciences. In this work, the HOMO-LUMO gap of graphene, Ti- or N-doped graphene is investigated by DFT methods. The adsorption of NO2, NO, and O2 on Ti- or N-doped graphene of different sizes is also explored. Results reveal that the interactions between gases (NO2, NO, and O2) and Ti- or N-doped graphenes is not affected by the size of graphene. The doped Ti greatly improves the interactions between gases and graphene whereas the doped N has no effect on those interactions. The HOMO- LUMO gap of Ti-doped graphene can be modulated by adsorption of the gases. The cross effect of the NO and O2 is also investigated, and it is demonstrated that Ti-doped graphene has specific interactions with NO2. Thus, Ti-doped graphene can be a candidate for NO2 sensor materials. Furthermore, doping the graphene with Ti or N improves the sensitivity of the sheets toward NO2, which can be trapped and detected by the intrinsic graphene. Efficient sensors are rationally designed to diversify their applications in environmental science and engineering.

Serum Levels of Human MIC-1/GDF15 Vary in a Diurnal Pattern, Do Not Display a Profile Suggestive of a Satiety Factor and Are Related to BMI.

The TGF-b superfamily cytokine MIC-1/GDF15 circulates in the blood of healthy humans. Its levels rise substantially in cancer and other diseases and this may sometimes lead to development of an anorexia/cachexia syndrome. This is mediated by a direct action of MIC-1/GDF15 on feeding centres in the hypothalamus and brainstem. More recent studies in germline gene deleted mice also suggest that this cytokine may play a role in physiological regulation of energy homeostasis. To further characterize the role of MIC-1/GDF15 in physiological regulation of energy homeostasis in man, we have examined diurnal and food associated variation in serum levels and whether variation in circulating levels relate to BMI in human monozygotic twin pairs. We found that the within twin pair differences in serum MIC-1/GDF15 levels were significantly correlated with within twin pair differences in BMI, suggesting a role for MIC-1/GDF15 in the regulation of energy balance in man. MIC-1/GDF15 serum levels altered slightly in response to a meal, but comparison with variation its serum levels over a 24 hour period suggested that these changes are likely to be due to bimodal diurnal variation which can alter serum MIC-1/GDF15 levels by about plus or minus 10% from the mesor. The lack of a rapid and substantial postprandial increase in MIC-1/GDF15 serum levels suggests that MIC1/GDF15 is unlikely to act as a satiety factor. Taken together, our findings suggest that MIC-1/GDF15 may be a physiological regulator of energy homeostasis in man, most probably due to actions on long-term regulation of energy homeostasis.

Computer simulation of biomolecule-biomaterial interactions at surfaces and interfaces.

Biomaterial surfaces and interfaces are intrinsically complicated systems because they involve biomolecules, implanted biomaterials, and complex biological environments. It is difficult to understand the interaction mechanism between biomaterials and biomolecules through conventional experimental methods. Computer simulation is an effective way to study the interaction mechanism at the atomic and molecular levels. In this review, we summarized the recent studies on the interaction behaviors of biomolecules with three types of the most widely used biomaterials: hydroxyapatite (HA), titanium oxide (TiO2), and graphene(G)/graphene oxide(GO). The effects of crystal forms, crystallographic planes, surface defects, doping atoms, and water environments on biomolecules adsorption are discussed in detail. This review provides valuable theoretical guidance for biomaterial designing and surface modification.

Comparisons of thyroid hormone, intelligence, attention, and quality of life in children with obstructive sleep apnea hypopnea syndrome before and after endoscopic adenoidectomy.

Objective. The aim of this study was to compare the differences in thyroid hormone, intelligence, attention, and quality of life (QoL) of children with obstructive sleep apnea hypopnea syndrome (OSAHS) before and after endoscopic adenoidectomy. Method. A total of 35 OSAHS children (21 males and 14 females with a mean age of 6.81 ± 1.08 years) were included in this study for analyzing the levels of thyroid hormone, intelligence, attention, and QoL. There were 22 children underwent endoscopic adenoidectomy with bilateral tonsillectomy (BT), while the other 13 children who underwent endoscopic adenoidectomy without bilateral tonsillectomy without BT. Results. Our results revealed no significant difference in serum free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) levels in OSAHS children before and after endoscopic adenoidectomy (all P > 0.05). However, there were significant differences in full-scale intelligence quotient (FIQ) (92.45 ± 5.88 versus 106.23 ± 7.39, P < 0.001), verbal intelligence quotient (VIQ) (94.17 ± 15.01 versus 103.91 ± 9.74, P = 0.006), and performance intelligence quotient (PIQ) (94.12 ± 11.04 versus 104.31 ± 10.05, P = 0.001), attention (98.48 ± 8.74 versus 106.87 ± 8.58, P < 0.001), and total OSA-18 scores (87.62 ± 17.15 versus 46.61 ± 10.15, P < 0.001) between before and after endoscopic adenoidectomy in OSAHS children. Conclusion. Our findings provided evidence that the intelligence, attention, and QoL of OSAHS children may be significantly improved after endoscopic adenoidectomy.

The anorectic actions of the TGFß cytokine MIC-1/GDF15 require an intact brainstem area postrema and nucleus of the solitary tract.

Macrophage inhibitory cytokine-1 (MIC-1/GDF15) modulates food intake and body weight under physiological and pathological conditions by acting on the hypothalamus and brainstem. When overexpressed in disease, such as in advanced cancer, elevated serum MIC-1/GDF15 levels lead to an anorexia/cachexia syndrome. To gain a better understanding of its actions in the brainstem we studied MIC-1/GDF15 induced neuronal activation identified by induction of Fos protein. Intraperitoneal injection of human MIC-1/GDF15 in mice activated brainstem neurons in the area postrema (AP) and the medial (m) portion of the nucleus of the solitary tract (NTS), which did not stain with tyrosine hydroxylase (TH). To determine the importance of these brainstem nuclei in the anorexigenic effect of MIC-1/GDF15, we ablated the AP alone or the AP and the NTS. The latter combined lesion completely reversed the anorexigenic effects of MIC-1/GDF15. Altogether, this study identified neurons in the AP and/or NTS, as being critical for the regulation of food intake and body weight by MIC-1/GDF15.

TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and body weight regulator.

The TGF-b superfamily cytokine MIC-1/GDF15 circulates in all humans and when overproduced in cancer leads to anorexia/cachexia, by direct action on brain feeding centres. In these studies we have examined the role of physiologically relevant levels of MIC-1/GDF15 in the regulation of appetite, body weight and basal metabolic rate. MIC-1/GDF15 gene knockout mice (MIC-1(-/-)) weighed more and had increased adiposity, which was associated with increased spontaneous food intake. Female MIC-1(-/-) mice exhibited some additional alterations in reduced basal energy expenditure and physical activity, possibly owing to the associated decrease in total lean mass. Further, infusion of human recombinant MIC-1/GDF15 sufficient to raise serum levels in MIC-1(-/-) mice to within the normal human range reduced body weight and food intake. Taken together, our findings suggest that MIC-1/GDF15 is involved in the physiological regulation of appetite and energy storage.

[Analysis on anti-vascular inflammatory mechanism in vitro of total flavones from Artemisia anomala].

OBJECTIVE: To study the impact of total flavones from Artemisia anomala (TFAS) on activation of macrophages, cell oxidative stress, auto-nitration of CuZn-SOD, platelet aggregation and isolated vascular tension. METHOD: LPS and IFN-gamma induced activation of macrophages and oxidative stress in rats; H2O2 and nitrite induced auto-nitration of CuZn-SOD; ADP, AA and collagen induced platelet aggregation in vitro in mice; PE stimulates isolated vascular tension; nitrite content of macrophages was measured by Griess assay; MTT assay and FRAP assay was applied for cell viability and total cell antioxidant capacity; auto-nitration of CuZn-SOD was measured by Western blot and colorimetric methods; platelet aggregation was detected by turbidimetry; and aorta ring relaxation was recorded by isolated vascular function experience devices for rats. RESULT: TFAS demonstrated dose dependence (25, 50, 100, 200 mg x L(-1)) on inhibiting induced macrophages NO production from generating, while increasing cell viability and total anti-oxidant capacity. Auto-nitration of CuZn-SOD was suppressed by TFAS in dose dependence (0.5, 5, 50 mg x L(-1)). TFAS showed an inhibitory effect on collagen-induced platelet aggregation at 50 mg x L(-1) and an endothelium-dependent relaxation effect on PE-induced vasoconstriction at 1 g x L(-1). CONCLUSION: TFAS shows effect on anti-inflammation, anti-oxidation, anti-nitration, anti-platelet aggregation and vasodilatation in experiment in vitro, which may inhibit vascular inflammatory by regulating multiple target points. It is among material bases for promoting blood circulation and removing blood stasis.

Anorexia/cachexia of chronic diseases: a role for the TGF-ß family cytokine MIC-1/GDF15.

Anorexia/cachexia is a common and currently mostly untreatable complication of advanced cancer. It is also a feature of a number of chronic diseases and can also occur as part of the normal ageing process. Over recent years, two different, but sometimes overlapping, processes have been identified to mediate anorexia/cachexia: those that act primarily on muscle reducing its mass and function, and processes that decrease nutrition leading to loss of both fat and muscle. In the case of at least some cancers, the latter process is sometimes driven by marked overexpression of macrophage inhibitory cytokine-1/growth differentiation factor 15 (MIC-1/GDF15). MIC-1/GDF15 is a transforming growth factor beta (TGF-ß) family cytokine that is found in the serum of all normal individuals at an average concentration of about 0.6 ng/ml. Its increased expression in both cancers and other diseases can result in 10-100-fold or more elevation of its serum levels. In experimental animals, serum MIC-1/GDF15 levels at the lower end of this range induce anorexia by direct actions of the circulating cytokine on feeding centres in the brain. Mice with tumours overexpressing MIC-1/GDF15 display decreased food intake, loss of lean and fat mass and cachexia. That this process also mediates anorexia/cachexia in humans is suggested by the fact that there is a direct correlation between the degree of serum MIC-1/GDF15 elevation and the amount of cancer-related weight loss, the first such relationship demonstrated. Further, in experimental animals, weight loss can be reversed by neutralisation of tumour-produced MIC-1/GDF15 with a specific monoclonal antibody, suggesting the possibility of effective therapy of patients with the devastating complication of anorexia/cachexia.

The TGF-ß superfamily cytokine, MIC-1/GDF15: a pleotrophic cytokine with roles in inflammation, cancer and metabolism.

Macrophage inhibitory cytokine-1 (MIC-1/GDF15) is associated with cardiovascular disease, inflammation, body weight regulation and cancer. Its serum levels facilitate the diagnosis and prognosis of cancer and vascular disease. Furthermore, its serum levels are a powerful predictor of all-cause mortality, suggesting a fundamental role in biological processes associated with ageing. In cancer, the data available suggest that MIC-1/GDF15 is antitumorigenic, but this may not always be the case as disease progresses. Cancer promoting effects of MIC-1/GDF15 may be due, in part, to effects on antitumour immunity. This is suggested by the anti-inflammatory and immunosuppressive properties of MIC-1/GDF15 in animal models of atherosclerosis and rheumatoid arthritis. Furthermore, in late-stage cancer, large amounts of MIC-1/GDF15 in the circulation suppress appetite and mediate cancer anorexia/cachexia, which can be reversed by monoclonal antibodies in animals. Available data suggest MIC-1/GDF15 may be an important molecule mediating the interplay between cancer, obesity and chronic inflammation.