Search

ObjectiveThe interleukin (IL)-12 cytokine family is closely related to the development of T helper cells, which are responsible for autoimmune disease enhancement or suppression. IL-12 family members are generally heterodimers and share three α-subunits (p35, p19, and p28) and two β-subunits (p40 and EBI3). However, a β-sheet p40 homodimer has been shown to exist and antagonize IL-12 and IL-23 signaling1. Therefore, we assumed the existence of a p40-EBI3 heterodimer in nature and sought to investigate its role in immune regulation.MethodsThe presence of the p40-EBI3 heterodimer was confirmed by ELISA, immunoprecipitation, and western blotting. A p40-EBI3 vector and p40-EBI3-Fc protein were synthesized to confirm the immunological role of this protein in mice with collagen-induced arthritis (CIA). The anti-inflammatory effects of p40-EBI3 were analyzed with regard to clinical, histological, and immune cell-regulating features in mice with CIA.ResultsClinical arthritis scores and the expression levels of proinflammatory cytokines (e.g., IL-17, IL-1β, IL-6, and TNF-α) were significantly attenuated in p40-EBI3-overexpressing and p40-EBI3-Fc-treated mice with CIA compared to vehicle-treated mice with CIA. Structural joint damage and vessel formation-related gene expression were also reduced by p40-EBI3 heterodimer treatment. In vitro, the p40-EBI3-Fc protein significantly suppressed the differentiation of Th17 cells and reciprocally induced CD4+CD25+Foxp3+(regulatory T) cells. p40-EBI3 also inhibited osteoclast formation in a concentration-dependent manner.ConclusionIn this study, p40-EBI3 ameliorated proinflammatory conditions both in vivo and in vitro. We propose that p40-EBI3 is a novel anti-inflammatory cytokine involved in suppressing the immune response through the expansion of Treg cells and suppression of Th17 cells and osteoclastogenesis.

Lung cancer is the leading cause of cancer deaths worldwide and most cancer patients receiving conventional chemotherapy suffer from severe side effects due to the non‐selective effects of chemotherapeutic drugs on normal cells. Targeted nanomaterials can obtain excellent accumulation at the tumor site through their active or passive targeting mechanisms, thereby reducing the toxicity of the drugs in various ways. In this study, hyaluronic acid (HA) which could specifically bind to CD44 on the surface of tumor cells, was used to modify amine‐caged platinum nanoclusters (Pt NCs‐NH2) to obtain targeting HA‐Pt NCs‐NH2. Based on the differential expression of CD44 on the surface of three lung cells (non‐small cell lung cancer cell H1299, small cell lung cancer cell H446, and embryonic lung fibroblast HFL1), HA‐Pt NCs‐NH2 can differentially enter the three cells and achieve their targeting of non‐small cell lung cancer cell (NSCLC) cells. Pt NCs significantly inhibited the proliferation, migration and invasion of NSCLC cells and induced their apoptosis in comparison of classical cisplatin and carboplatin, showing a bright future in early diagnosis and treatment of NSCLC., Hyaluronic acid‐functionalized platinum nanoclusters could differentially enter into three types of cells based on differential CD44 receptor expression. The nanocluster have shown specific targeting and inhibition behaviors on proliferation, invasion, and migration of NSCLC cells.

BACKGROUND/OBJECTIVES Premenstrual syndrome (PMS) is a disorder characterized by repeated emotional, behavioral, and physical symptoms before menstruation, and the exact cause and mechanism are uncertain. Hyperprolactinemia interferes with the normal production of estrogen and progesterone, leading to PMS symptoms. Thus, we judged that the inhibition of prolactin hypersecretion could mitigate PMS symptoms. MATERIALS/METHODS Hordeum vulgare L. extract (HVE), Chrysanthemum zawadskii var. latilobum extract (CZE), and Lomens-P0 the mixture of these extracts were tested in subsequent experiments. The effect of extracts on prolactin secretion at the in vitro level was measured in GH3 cells. Nitric oxide and pro-inflammatory mediator expression were measured in RAW 264.7 cells to confirm the anti-inflammatory effect. Also, the hyperprolactinemic Institute for Cancer Research (ICR) mice model was used to measure extract effects on prolactin and hormone secretion and uterine inflammation. RESULTS Anti-inflammatory effects of and prolactin secretion suppress by HVE and CZE were confirmed through in vitro experiments (P < 0.05). Treatment with Lomens-P0 inhibited prolactin secretion (P < 0.05) and restored normal sex hormone secretion in the hyperprolactinemia mice model. In addition, extracts significantly inhibited the expression of pro-inflammatory biomarkers, including interleukin-1β, and -6, tumor necrosis factor-α, inducible nitric oxide synthase, and cyclooxygenase-2 (P < 0.01). We used high-performance liquid chromatography analyses to identify tricin and chlorogenic acid as the respective components of HVE and CZE that inhibit prolactin secretion. The Lomens-P0, which includes tricin and chlorogenic acid, is expected to be effective in improving PMS symptoms in the human body. CONCLUSIONS The Lomens-P0 suppressed the prolactin secretion in hyperprolactinemia mice, normalized the sex hormone imbalance, and significantly suppressed the expression of inflammatory markers in uterine tissue. This study suggests that Lomens-P0 may have the potential to prevent or remedy materials to PMS symptoms.

Ning Wang,1,* Yanqi Peng,1,* Lu Wang,1 Lin Song,2 Bo Sun,2 Junxiang Wei,3 Ting Wang,4 Yang Mi,3 Wei Cui1 1Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 2Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, People’s Republic of China; 3The Second Department of Obstetrics, Northwest Women and Children’s Hospital, Xi’an, People’s Republic of China; 4Department of Respiratory Medicine, Xi’an No.4 Hospital, Xi’an, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yang MiThe Second Department of Obstetrics, Northwest Women and Children’s Hospital, 1616 Yanxiang Road, Xi’an, Shaanxi, 710065, People’s Republic of ChinaTel +86-13700222172Email miyangmm@163.comWei CuiDepartment of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Road, Xi’an, Shaanxi, 710061, People’s Republic of ChinaTel +86-13609281695Email doctorweiweixjtu@126.comPurpose: To study the risk factors of gestational diabetes mellitus (GDM) heterogeneity, and to evaluate the correlation between the risk factors and obesity.Methods: We performed a case–control study of 452 women with GDM and 516 women with normal glucose tolerance (NGT) at the first and second trimester. We defined GDM women as GDM-resistance subtype, GDM-dysfunction subtype, and GDM-mixed subtype, according to their simultaneous insulin-release test with predominant insulin-sensitivity defect, insulin-secretion defect, or both defects.Results: We found that higher maternal age, family history of diabetes, the elevated level of fasting blood glucose in the first trimester (≥ 5.1 mmol/L) were risk factors of all GDM subtypes. Pre-pregnancy overweight/obesity and the increased gestational weight gain (GWG) in the first-trimester are risk factors of the GDM-resistance subtype. Indicators including younger age at first menstruation, the elevated levels of alanine aminotransferase (ALT), total bile acid (TBA), triglyceride (TG), and the decreased level of high-density lipoprotein cholesterol (HDL-C) are risk factors of the GDM-resistance subtype. However, the associations between those risk factors and GDM-resistance subtype attenuated after adjusted by pre-pregnancy body mass index (pre-BMI) and gestational weight gain (GWG) in the first trimester. Nonalcoholic fatty liver disease (NAFLD) and the improved level of TG are independent risk factors for the GDM-resistance subtype and the GDM-mixed subtype, respectively.Conclusion: Women with GDM exhibited heterogeneity based on glycemic physiology and their risk factors are not all the same. Some obesity-related risk factors are specific to the GDM-resistance subtype, which are mediated by pre-pregnancy overweight/obesity and the elevated GWG the first-trimester.Keywords: pregnancy, pre-pregnancy BMI, gestational weight gain, obesity, insulin resistance, insulin secretion

To examine the effect of pre-pregnancy maternal body mass index (BMI) on neonatal weight outcomes of twin infants who were conceived by assisted reproductive technology (ART). A 10-year (2006–2015) Chinese sample of 3431 mothers and their twin infants conceived by ART from a retrospective cohort were included. The effects of pre-pregnancy maternal BMI on gestational age and birth weight were assessed by generalized linear model and generalized estimating equation model. Compared with a normal weight group, pre-pregnancy maternal underweight was associated with lower birth weight and increased risk of small for gestational age (SGA) in twins conceived by ART (birth weight: difference −59.22 g, 95% CI −93.16 to −25.27 g; SGA: RR 1.25, 95% CI 1.09 to 1.43). Pre-pregnancy maternal obesity was associated with higher birth weight and increased risk of preterm birth (birth weight: difference 65.82 g, 95% CI 10.66 to 120.99 g; preterm birth: RR 1.19, 95% CI 1.03–1.37). A nonlinear relationship between pre-pregnancy maternal BMI and SGA was observed. The risk of SGA decreased with the pre-pregnancy maternal BMI up to the turning point (BMI = 21) (RR 0.90, 95% CI 0.86–0.95). Among mothers undergoing ART, pre-pregnancy maternal obesity is associated with higher birth weight and higher risk of preterm birth for twin pregnancy, and pre-pregnancy maternal underweight is associated with lower birth weight and higher risk of SGA. Women preparing for ART should maintain a normal BMI to lower the chances of adverse neonatal outcomes.

The large-scale Xi’an longitudinal mother–child cohort study has started to enroll pregnant women who attended Northwest Women’s and Children’s Hospital (NWCH) for antenatal care in early pregnancy (less than 20 weeks’ gestation) from January 2013 and the enrollment will be ended in January 2023. We aimed to investigate the role of external factors (i.e., diet and environment) and internal (i.e., biological, genetic and epigenetic) on the short- and long-term outcomes of mothers and children up to at least 12 years. Mothers completed all routine prenatal care during pregnancy and four times of follow-up at 42 days, 3, 6 and 12 years after delivery, respectively. For children, birth information were obtained from routine medical records and the follow-up information were obtained from child health care clinics of NWCH at age 42 days, 6, 12 and 24 months, then by interviewing mothers every two years until 12 years old. A range of data (including biological, demographic, birth outcomes/birth defects and nutritional factors from both maternal and off-spring) were collected by both interviews and laboratory tests. By June 30th 2019, a total of 114,946 mothers and 124,454 live births had been recruited.

The mechanism of generation of antigen-specific regulatory T cells (Treg) is not fully understood yet. This study aimed to investigate the role of intestinal epithelial cell (IEC)-derived CD83 in the Treg generation in the intestine. In this study, the role of CD83 in the generation of Tregs was assessed in a cell-culture model and a food allergy (FA) mouse model. We found that mouse IECs expressed CD83; its levels were markedly lower in sensitized mice. Mice with CD83-deficient IECs failed to induce Tregs in the intestine. CD83 promoted the transforming growth factor-β-inducible early gene 1 (TIEG1) expression in CD4+ T cells. Toll-like receptor 4 (TLR4)/myeloid differentiation protein-2 (MD-2) complex mediated the effects of CD83 on the expression of TIEG1. Activation of the CD83/TLR4/MD-2/TIEG1 promoted the Treg generation. Concomitant administration of CD83 and specific antigens, but not either one alone, efficiently inhibited experimental FA via inducing the Treg generation in the intestine. In Conclusion, IEC expresses CD83 that is low in sensitized mice. Concomitant administration of CD83 and specific antigens efficiently inhibits FA in a murine model via inducing Tregs in the intestine. The data suggest that CD83 has translation potential in the treatment of FA.

Background Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) and increases the risk of subsequently developing chronic kidney disease. Angiogenesis has been shown to play an important role in reducing renal injury after ischemia reperfusion. In this study, we investigated whether IMD could reduce renal IRI by promoting angiogenesis. Methods The kidneys of Wistar rats were subjected to 45 min of warm ischemia followed by 24 h of reperfusion. IMD was overexpressed in vivo using the vector pcDNA3.1-IMD transfected by an ultrasound-mediated system. The renal injury after ischemia reperfusion was assessed by detection of the serum creatinine concentration and histologic examinations of renal tissues stained by PAS and H&E. Real-time PCR and Western blotting were used to determine the mRNA and protein levels, respectively. Histological examinations were used to assess the expression of CD31, MMP2, MMP9, ET-1, VEGF and VEGFR2 in tissues. Results Renal function and renal histological damage were significantly ameliorated in IMD-transfected rats after ischemia reperfusion. Compared to the IRI, IMD significantly promoted angiogenesis. IMD also upregulated the protein and mRNA expression levels of VEGF and VEGFR2 and downregulated the expression level of MMP2, MMP9 and ET-1. Conclusion IMD could protect the kidney after renal ischemia-reperfusion injury by promoting angiogenesis and reducing the destruction of the perivascular matrix.

Emerging evidence has implicated poly-(ADP-ribose) polymerase 1 (PARP-1), a transcriptional coregulator, in a variety of inflammatory diseases. In the current study, the role of PARP-1 in neuropathic pain and the underlying mechanisms were investigated. Neuropathic pain was determined by assessing the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) following lumbar 5 spinal nerve ligation (SNL) in male rates. Western blotting, qRT-PCR, immunohistochemistry, chromatin immunoprecipitation (ChIP), and Co-IP assays were performed to elucidate the mechanisms. The results showed that SNL resulted in a significant increase in the expression and activation of PARP-1 in the ipsilateral L4/5 dorsal root ganglia (DRG) and spinal dorsal horn, which occurred on day one, reached peak on day 7, and persisted more than 2 weeks after surgery. Double immunofluorescence staining revealed that PARP-1 was expressed exclusively in DRG A-type and C-type neurons. In the spinal cord, PARP-1 mainly colocalized with the neuronal marker NeuN and the astrocytic marker GFAP specifically in the superficial lamina. Prior intrathecal (i.t.) injection of PJ-34, a PARPs inhibitor, or Tiq-A, a specific PARP-1 inhibitor, dose-dependently prevented the reductions in PWT and PWL following SNL. Established neuropathic pain-like hypersensitivity was also attenuated with i.t. injection of PJ-34 and Tiq-A starting on day 7 following SNL, a timepoint at which neuropathic pain was fully established. SNL-induced mechanical allodynia and thermal hyperalgesia were also alleviated by i.t. injection of PARP-1 siRNA following a reduction in PARP-1 expression in the dorsal horn. Moreover, the SNL-induced increases in TNF-α protein and mRNA in the dorsal horn and DRG were dramatically suppressed by i.t. injection of Tiq-A or PARP-1 siRNA. The i.t. lipopolysaccharide (LPS)-induced increase in the production of TNF-α in the dorsal horn was also inhibited by prior to i.t. injection of PARP-1 siRNA. Results of ChIP assay showed that SNL-induced PARP-1 activation promoted the binding of NF-κB p65 with the TNF-α promoter in the dorsal horn and that PARP-1 inhibition reduced this binding and suppressed TNF-α expression. Co-IP assay revealed that SNL caused a significant increase in the level of histone H1 poly(ADP)–ribosylation. Together, these results indicate that PARP-1-regulated TNF-α expression in the DRG and spinal dorsal horn following SNL contributes to the development and maintenance of neuropathic pain. Targeting PARP-1 might be a promising therapeutic strategy for the treatment of the chronic pain.

Background: Helicobacter pylori-induced DNA damage and impaired homologous recombination repair are vital molecular mechanisms for gastric cancer, which mainly count on its virulence factors cytotoxic-associated gene A (CagA) and vacuolating cytotoxin A (VacA). However, the relationship between H. pylori CagA EPIYA motifs and vacA genotypes with DNA damage and homologous recombination repair markers is still not clear. Methods: H. pylori positive and negative gastric biopsies were taken from 165 subjects with different gastric precancerous pathologic stages, and DNA damage marker γH2AX and key homologous recombination repair proteins (CtIP and Rad51) were investigated for their association with H. pylori CagA EPIYA motifs and vacAs-, m-, i-, and d-region genotypes and histology (Sydney classification). Results: Out of 165 patients, 78 were identified as H. pylori-positive. CagA EPIYA motifs were identified as AB, ABC, and ABD in 2 (3.3%), 21 (35%), and 37 (61.7%) patients, respectively, while vacA alleles were identified as: s1, s2, m1, m2, i1, i2, d1, and d2 in 50 (89.3%), 6 (10.7%), 24 (42.9%), 32 (57.1%), 45 (80.4%), 11 (19.6%), 40 (71.4%), and 16 (28.6%) patients, respectively. vacAs1m1i1d1, s1m2i1d1, and s1m2i2d2 were the most prevailing genotypes. γH2AX was highly localized in H. pylori-positive tissues with corresponding CagA EPIYA motifs and vacA genotypes, while Rad51 and CtIP signals were weak. Conclusion: H. pylori were positively correlated with the DNA damage marker in precancerous lesions, but were negatively correlated with the key homologous recombination repair proteins, which may be due to the specific CagA EPIYA motifs and vacA genotypes.

Purpose Osteoarthritis (OA) of the temporomandibular joint (TMJ) elicits cartilage and subchondral bone defects. Growth hormone (GH) promotes chondrocyte growth. The aim of this study was to evaluate the efficacy of intra-articular injections of GH to treat TMJ-OA. Materials and methods Monosodium iodoacetate (MIA) was used to induce OA in the TMJs of rats. After confirming the induction of OA, recombinant human GH was injected into the articular cavities of rats. Concentrations of GH and IGF-1 were measured in the blood and synovial fluid, and OA grades of cartilage and subchondral bone degradation were recorded by histological examination and micro-computed tomography. Results MIA-induced OA in the rat TMJ upregulated insulin-like growth factor-1 (IGF-1) rather than GH levels. GH and IGF-1 concentrations were increased after local injection of GH, compared with controls. Locally injected GH lowered osteoarthritic scores in the cartilage and subchondral bone of the TMJ. Conclusion Intra-articular injection of GH improved OA scores in rat TMJs in both cartilage and subchondral bone of the condyles without affecting condylar bone growth. These results suggest that intra-articular injection of human GH could be a suitable treatment option for TMJ-OA patients in the future.

Analgesic tolerance and hyperalgesia hinder the long-term utility of opioids. We examined whether spinal high mobility group box 1 (HMGB1) is involved in morphine tolerance and its underlying mechanisms by using a model of repeated intrathecal (i.t.) injections of morphine. The results showed that chronic i.t. morphine exposure led to increased expression of HMGB1, Toll-like receptor 4 (TLR4), and receptor for advanced glycation end products (RAGE) and their mRNAs in the dorsal horn. Morphine challenge also promoted HMGB1 expression and release in cultured spinal neurons, but these effects were inhibited by TAK-242, naloxone (antagonists of TLR4), and TLR4 siRNA. Intrathecal coadministration of morphine with TAK-242 or PDTC (inhibitor of NF-κB activation) also reduced HMGB1 expression in the spinal cord. Repeated i.t. coinjections of morphine with glycyrrhizin (GL, an HMGB1 inhibitor) or HMGB1 siRNA prevented reduction of the maximal possible analgesic effect (MPAE) of morphine and alleviated morphine withdrawal-induced hyperalgesia. The established morphine tolerance and hyperalgesia were partially reversed when i.t. injections of GL or HMGB1 antibody started at day 7 of morphine injection. Repeated i.t. injections of morphine with HMGB1 siRNA inhibited the activation of NF-κB, but not that of JNK and p38. A single i.t. injection of HMGB1 in naïve rats caused pain-related hypersensitivity and reduction in MPAE. Moreover, phosphorylated NF-κB p65, TNF-α, and IL-1β levels in the dorsal horn were upregulated following this treatment, but this upregulation was prevented by coinjection with TAK-242. Together, these results suggest that morphine-mediated upregulation of spinal HMGB1 contributes to analgesic tolerance and hyperalgesia via activation of TLR4/NF-κB signaling, and the HMGB1 inhibitor might be a promising adjuvant to morphine in the treatment of intractable pain in the clinic. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-019-00800-w) contains supplementary material, which is available to authorized users.

An exoskeleton system can be an effective ergonomic intervention for mitigating the risks of developing work-related musculoskeletal disorders, yet little attention is given to the effects of its application on physical risk factors and subjective responses. Therefore, the objective of this study was to examine the effects of a passive exoskeleton system on spinal biomechanics and subjective responses during manual repetitive handling tasks among construction workers. Muscle activity of the Thoracic Erector Spinae (TES), Lumbar Erector Spinae (LES) at L3 vertebrae level, Rectus Abdominis (RA), and External Oblique (EO) during the repetitive handling tasks were measured by surface electromyography (sEMG). Additionally, the Borg categorical rating scale (Borg CR 10), local perceived pressure (LPP), and system usability scale (SUS) were used to measure the ratings of perceived discomfort, perceived musculoskeletal pressure, and system usability, respectively. Our results found that: (1) the use of the passive exoskeleton system significantly reduced LES muscle activity (11–33% MVC), with a greater reduction in LES muscle activity (32.71% MVC) for the heaviest lifting load; (2) the use of the passive exoskeleton system significantly reduced perceived discomfort scores (42.40%) of the lower back for the heaviest lifting load; (3) increased lifting load significantly increased LPP scores of the shoulder, lower back, and leg body parts; and (4) majority of the participants rated the passive exoskeleton system as having acceptable usability. The findings of these results indicate that the developed passive exoskeleton system could reduce the internal muscle force, extensor moments, and spinal forces in the lumbar region.

In the present study, we investigated the effects of Galla Rhois (GR) on obesity and gene expression. We prepared a GR extract and various solvent fractions and evaluated the degree to which they inhibited adipocyte differentiation and adipogenesis in vitro. Among them, the GR ethyl acetate fraction (GE) had the lowest EC50 for adipocyte differentiation and adipogenesis and thus was selected for in vivo experiments. We induced obesity in C57BL/6 mice by providing them a high-fat diet (HFD). Then, GE (10-40 mg/kg) or orlistat (positive control, 4 mg/kg) was orally administered daily for six weeks. Mean body weights and weight gain were significantly lower in the GE40 group (40 mg/kg of GE) compared with the HFD group (p < 0.05). The most significant changes in serum glucose, total cholesterol, and triglyceride levels were confirmed in the GE40 group (p < 0.05). Epididymal fat was weighed and stained for body fat measurement, and significant differences were recorded from GE10 to GE40 (p < 0.05). Finally, 3T3-L1 pre-adipocytes were treated with GE, and cDNA from these cells was used for microarray analysis and qRT-PCR. Microarray analysis revealed 13 genes up-regulated and 21 genes down-regulated by GE. From the qRT-PCR analysis, we found that GE altered the mRNA expression of eosinophil peroxidase, glucose-dependent insulinotropic polypeptide receptor, and apolipoprotein B. Based on this study, we suggest that GR could be developed as an anti-obesity therapeutic agent.

Background: To study the discrepancy of the insulin sensitivity alteration pattern, circulating fibroblast growth factor (FGF21) levels and FGF21 signaling in visceral white adipose tissue (vWAT) of gestational diabetes mellitus (GDM) subtypes.Methods: 26 GDM women with either a predominant of insulin-secretion defect (GDM-dysfunction, n = 9) or insulin-sensitivity defect (GDM-resistance, n = 17)] and 13 normal glucose tolerance (NGT) women scheduled for caesarean-section at term were studied. Plasma and vWAT samples were collected at delivery.Results: The insulin sensitivity was improved from the 2nd trimester to delivery in the GDM-resistance group. Elevated circulating FGF21 concentration at delivery, increased FGF receptor 1c and decreased klotho beta gene expressions, enhanced ERK1/2 phosphorylation, and increased GLUT1, IR-B, PPAR-γ gene expressions in vWAT were found in the GDM-resistance group as compared with the NGT group. The circulating FGF21 concentration was negatively correlated with fasting blood glucose (r = -0.574, P < 0.001), and associated with the GDM-resistance group (r = 0.574, P < 0.001) in pregnant women at delivery. However, we observed no insulin sensitivity alteration in GDM-dysfunction and NGT groups during pregnancy. No differences of plasma FGF21 level and FGF21 signaling in vWAT at delivery were found between women in the GDM-dysfunction and the NGT group. Conclusions: Women with GDM heterogeneity exhibited different insulin sensitivity alteration patterns. The improvement of insulin sensitivity may relate to the elevated circulating FGF21 concentration and activated FGF21 signaling in vWAT at delivery in the GDM-resistance group.Trial registration: ChiCTR, ChiCTR 1900026735, registered 20 October 2019, https://www.chictr.org.cn/25/showproj.aspx?proj=44559

Hepatocellular carcinoma (HCC) is one of the most fatal cancers worldwide. In this article, we show that expression of abnormal spindle‐like microcephaly‐associated protein (ASPM) is up‐regulated in liver cancer samples, and this up‐regulation is significantly associated with tumor aggressiveness and reduced survival times of patients. Down‐regulation of ASPM expression inhibits the proliferation, invasion, migration and epithelial‐to‐mesenchymal transition of HCC cells in vitro and inhibits tumor formation in nude mice. ASPM interacts with disheveled‐2 (Dvl2) and antagonizes autophagy‐mediated Dvl2 degradation by weakening the functional interaction between Dvl2 and the lipidated form of microtubule‐associated proteins 1A/1B light chain 3A (LC3II), thereby increasing Dvl2 protein abundance and leading to Wnt/β‐catenin signaling activation in HCC cells. Thus, our results define ASPM as a novel oncoprotein in HCC and indicate that disruption of the Wnt–ASPM–Dvl2–β‐catenin signaling axis might have potential clinical value., The abnormal spindle‐like microcephaly‐associated protein (ASPM) promotes hepatocellular carcinoma progression by activating Wnt/β‐catenin signaling. ASPM interacts with disheveled‐2 (Dvl2) and antagonizes autophagy‐mediated Dvl2 degradation by weakening the functional interaction between Dvl2 and the lipidated form of microtubule‐associated proteins 1A/1B light chain 3A (LC3II), thereby increasing Dvl2 protein abundance and leading to Wnt/β‐catenin signaling activation in HCC cells.

The abundance and type of immune cells in the tumor microenvironment (TME) significantly influence immunotherapy and tumor progression. However, the role of immune cells in the TME of gastric cancer (GC) is poorly understood. We studied the correlations, proportion, and infiltration of immune and stromal cells in GC tumors. Data analyses showed a significant association of infiltration levels of specific immune cells with the pathological characteristics and clinical outcomes of GC. Furthermore, based on the difference in infiltration levels of immune and stromal cells, GC patients were divided into two categories, those with “immunologically hot” (hot) tumors and those with “immunologically cold” (cold) tumors. The assay for transposase‐accessible chromatin using sequencing and RNA sequencing analyses revealed that the hot and cold tumors had altered epigenomic and transcriptional profiles. Claudin‐3 (CLDN3) was found to have high expression in the cold tumors and negatively correlated with CD8+ T cells in GC. Overexpression of CLDN3 in GC cells inhibited the expression of MHC‐I and CXCL9. Finally, the differentially expressed genes between hot and cold tumors were utilized to generate a prognostic model, which predicted the overall survival of GC as well as patients with immunotherapy. Overall, we undertook a comprehensive analysis of the immune cell infiltration pattern in GC and provided an accurate model for predicting the prognosis of GC patients., Immune hot and cold tumors showed the difference in epigenetic and transcriptomic alterations. Claudin 3 (CLDN3) was negatively correlated with the infiltration of CD8+ T cells. Overexpression of CLDN3 in gastric cancer (GC) cells inhibited the expression of MHC‐I and CXCL9. The prediction model performed well in predicting overall survival of patients with GC and patients with immunotherapy treatment.

Intermedin (IMD) is a member of the calcitonin gene-related peptide (CGRP) superfamily and a pro-angiogenic factor. In the present study, we identified activation of the Wnt/β-catenin signaling pathway by IMD. Adding CoCl2 HUVECs was used to establish an in vitro model. The migration of HUVECs was measured by wound healing assays and transwell migration assays. Capillary formation was measured using tube formation assays. Immunocytochemistry (ICC) analysis was used to evaluate VEGF and RAMP2 expression in HUVECs. The relevant signaling molecules were detected with western blot. Our study shows that IMD could promote H/R impaired HUVECs migration and tube formation in vitro. On the other hand, inhibition of Wnt/β-catenin signaling led to the suppression of this promotion of migration and tube formation. This result suggests that Wnt/β-catenin signaling is correlated to IMD induced angiogenesis. Analysis of results from ICC assays indicated that IMD works through increasing levels of VEGF and RAMP2. Meanwhile, the Wnt/β-catenin signaling specific inhibitor IWR-1-endo was shown to down-regulate VEGF and RAMP2 expression. Western blot results further confirmed the signaling mechanism by which IMD promotes angiogenesis. Thus, Wnt/β-catenin signaling plays an important role in IMD induced neovascularization. The data further suggest that the PI3K axis contributes positively downstream.

Purpose Bulbar injury is the most common type of urethral injury. This study investigated the efficacy and safety of a novel technique, local urethral flushing, in preventing stricture formation after blunt bulbar urethra injuries. Materials and Methods This retrospective study included 205 males diagnosed with straddle injury-induced bulbar urethra injury at the Shanxi Bethune Hospital and First Hospital of Shanxi Medical University between January 2015 and January 2019. Patients were diagnosed by retrograde urethrography and classified as partial or complete urethral rupture according to the urethral integrity after injury. Complete urethral rupture patients received suprapubic cystostomy and received urethroplasty 3 months later. Patients with partial urethral rupture underwent endoscopic urethral realignment by cystoscopic guide-wire guided catheterization. Patients with both injury types were divided into 3 groups. The treatment groups received urethral flushing with 0.05% dexamethasone through a secondary ureteral catheter that locked at the urethral lesion. The blank control groups received normal saline. The negative control groups had only a single ureteral catheter placed. Patients were assessed for pain during catheterization, infection, and stenosis, and followed for at least 2 years. Results Stenosis rates and length were significantly reduced in the normal saline groups, and even further reduced in the dexamethasone groups. The negative control groups had significantly higher infection rates than patients in the dexamethasone or saline groups. Conclusions Local urethral flushing with dexamethasone could significantly decrease urethral stenosis rates and severity without increasing patients’ discomfort or infection risk., Graphical Abstract

Summary Characterized by steatosis, inflammation and fibrosis, non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder. As a major lipid droplet-binding protein, Plin5 has been reported to have multiple effects on metabolism, but the effect of Plin5 deficiency on NAFLD is unknown. Plin5 knockout mice and wild-type mice were used to investigate the role of Plin5 in the progression of NAFLD by feeding a high-fat diet (HFD) for 20 weeks. Plin5 deficiency improved obesity induced by the HFD and altered glucose tolerance. Histological examination revealed that Plin5 deficiency alleviated hepatic steatosis and fibrosis induced by the HFD. Plin5 deficiency was also associated with a significant change in lipid metabolism-associated molecules. Further studies of these molecules indicated that Plin5 deficiency activated the expression of AMP-activated protein kinase and inhibited the core regulator of lipogenesis, sterol regulatory element binding protein 1 and its downstream lipid synthesis-related genes. These findings suggest that Plin5 deficiency ameliorates NAFLD by regulating lipid metabolism and inhibiting lipogenesis, and may provide a new strategy for the treatment of NAFLD.

Background An increased incidence of monozygotic twinning after a blastocyst transfer has been previously reported in assisted reproductive technology treatment. It is uncertain whether this phenomenon is due to the extended culture time, culture medium, or inherent blastocyst parameters. Objective This study aimed to investigate the association between blastocyst parameters (in vitro culture time, blastocyst stage, and inner cell mass and trophectoderm grading) and the incidence of monozygotic twinning after assisted reproductive technology. Study Design This was a retrospective cohort study employing data from a multicenter, large, electronic database from 4 academic hospitals. All clinical pregnancies after a single blastocyst transfer between January 2014 and February 2020 were included. Blastocyst morphology was evaluated based on the Gardner grading system, considering the blastocyst stage, and inner cell mass and trophectoderm grading (grades A, B, and C). Monozygotic twinning was defined as ≥2 fetal heartbeats in a single gestational sac or 2 gestational sacs with sex concordance at birth. The multivariable predicted marginal proportions from logistic regression models were used to compute adjusted relative risks for the association between blastocyst parameters and the incidence of monozygotic twinning. Results The overall monozygotic twinning rate was 1.53% (402 of 26,254 cases). The monozygotic twinning was not associated with the culture time in vitro (day 5 vs day 6) or blastocyst stage (early, blastocyst, expanded, hatching, and hatched). Alternatively, monozygotic twinning was associated with lower inner cell mass grading (B vs A: adjusted relative risk, 1.67 [95 % confidence interval, 1.28–2.25]; C vs A: adjusted relative risk, 1.98 [95% confidence interval, 1.18–3.11]) and higher trophectoderm grading (B vs C: adjusted relative risk, 1.38 [95% confidence interval, 1.03–1.92]; A vs C: adjusted relative risk, 2.14 [95% confidence interval, 1.45–3.20]). The incidence of monozygotic twinning was the lowest in blastocysts with grade A inner cell mass and grade B or C trophectoderm (0.82%, as the reference) and the highest in blastocysts with grade B or C inner cell mass and grade A trophectoderm (2.40%; adjusted relative risk, 2.62; 95% confidence interval, 1.60–4.43). The incidence of monozygotic twinning in blastocysts with consistent inner cell mass or trophectoderm grading was somewhere in between (both A: 1.58%; adjusted relative risk, 1.86 [95% confidence interval, 1.23–3.04]; both B or C: 1.59%; adjusted relative risk, 1.84 [95% confidence interval, 1.29–2.90]). Conclusion Higher risk of monozygotic twinning was associated with blastocyst morphology specific to those blastocysts with loosely arranged inner cell mass cells combined with tightly packed trophectoderm cells.

Background The prevalence of hypertension is high and rising in China, but most people with hypertension do not have their blood pressure under control. This study investigated hypertension awareness, treatment, and control and their associated factors among Chinese adults. Methods Data collected from the 2011 China Health and Nutrition Survey (CHNS) from 12,991 Chinese adults were used. Hypertension was defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, self-reported prior diagnosed hypertension, or taking antihypertensive medications. Hypertension awareness, treatment, and control were defined as a self-reported diagnosis of hypertension, current use of antihypertensive medication, and blood pressure Results Overall, 3579 (27.6%) of the CHNS adult participants had hypertension, of whom 55.7% were aware of their diagnosis, 46.5% were treated with antihypertensive medications, but only 20.3% had their blood pressure under control. Higher hypertension treatment was associated with older age (OR = 2.57; 95%CI, 1.65–4.02), urban residency (1.50; 1.14–1.97), living in the Eastern region (1.52; 1.14–2.01), and being overweight/obese (1.99; 1.39–2.84). Hypertension awareness was associated with similar factors as hypertension treatment but was also associated with being female (1.37, 1.12–1.66). Poor hypertension control was associated with being overweight/obese (0.56; 0.42–0.76) and minority ethnicity (0.52; 0.31–0.86). Conclusion Hypertension is a major public health challenge in China. The prevalence of hypertension awareness, treatment, and control are still low despite existing public health policies and programs to reduce the burden of hypertension. More intensive hypertension screening and treatment programs are warranted in China.

Background For most women who have had a previous cesarean section, vaginal birth after cesarean section (VBAC) is a reasonable and safe choice, but which will increase the risk of adverse outcomes such as uterine rupture. In order to reduce the risk, we evaluated the factors that may affect VBAC and and established a model for predicting the success rate of trial of the labor after cesarean section (TOLAC). Methods All patients who gave birth at Northwest Women’s and Children’s Hospital from January 2016 to December 2018, had a history of cesarean section and voluntarily chose the TOLAC were recruited. Among them, 80% of the population was randomly assigned to the training set, while the remaining 20% were assigned to the external validation set. In the training set, univariate and multivariate logistic regression models were used to identify indicators related to successful TOLAC. A nomogram was constructed based on the results of multiple logistic regression analysis, and the selected variables included in the nomogram were used to predict the probability of successfully obtaining TOLAC. The area under the receiver operating characteristic curve was used to judge the predictive ability of the model. Results A total of 778 pregnant women were included in this study. Among them, 595 (76.48%) successfully underwent TOLAC, whereas 183 (23.52%) failed and switched to cesarean section. In multi-factor logistic regression, parity = 1, pre-pregnancy BMI 2, cervical score ≥ 5, a history of previous vaginal delivery and neonatal birthweight Conclusion The TOLAC was useful to reducing the cesarean section rate. Being primiparous, not overweight or obese, having a cervical score ≥ 5, a history of previous vaginal delivery or neonatal birthweight

Objective To assess the effects of various treatment planning parameters to identify the optimal gap distance for precise two-segment total body irradiation (TBI) using helical tomotherapy (HT) with fixed jaw mode. Methods and materials Data of a treatment plan for 8 acute leukemia patients (height range: 109–130 cm) were analyzed. All patients underwent total-body computed tomography (CT) with 5-mm slice thickness. A lead wire, placed at 10 cm above the patella, was used to mark the boundary between the two segments. Target volumes and organs at risk were delineated using a Varian Eclipse 10.0 physician’s workstation. Different distances between the lead wire and the boundary of the two targets were used. CT images were transferred to the HT workstation to design the treatment plans, by adjusting parameters, including the field width (FW; 2.5 cm, and 5 cm), pitch (0.287 and 0.430), modulation factor (1.8). The plans were superimposed to analyze the dose distributions in the overlap region when varying target gap distances, FWs, pitches to determine the optimal combinations. Results The pitch did not affect the dose distribution in the overlap region. The dose distribution in the overlap region was mostly homogeneous when the target gap distance was equal to the FW. Increased FW diminished the effect of the target gap distance on the heterogeneous index of the overlap region. Conclusions In two-segment TBI treatments by HT with Helix mode, a gap distance equal to the FW may achieve optimal dose distribution in the overlap region.

Oxidative stress is considered a key hallmark of preeclampsia, which causes the dysregulation of trophoblast cells, and it contributes to the pathogenesis of preeclampsia. Emerging evidence has suggested bromodomain-containing protein 4 (BRD4) as a key regulator of oxidative stress in multiple cell types. However, whether BRD4 participates in regulating oxidative stress in trophoblast cells remains undetermined. The current study was designed to explore the potential function of BRD4 in the regulation of oxidative stress in trophoblast cells. Our data revealed that BRD4 expression was elevated in trophoblast cells stimulated with hydrogen peroxide. Exposure to hydrogen peroxide caused marked decreases in the levels of proliferation and invasion but promoted apoptosis and the production of ROS in trophoblast cells. Knockdown of BRD4, or treatment with a BRD4 inhibitor, markedly increased the levels of cell proliferation and invasion and decreased apoptosis and ROS production following the hydrogen peroxide challenge. Further data indicated that suppression of BRD4 markedly decreased the expression levels of Keap1, but increased the nuclear expression of Nrf2 and enhanced Nrf2-mediated transcriptional activity. BRD4 inhibition-mediated protective effects were markedly reversed by Keap1 overexpression or Nrf2 inhibition. Overall, these results demonstrated that BRD4 inhibition attenuated hydrogen peroxide-induced oxidative stress injury in trophoblast cells by enhancing Nrf2 activation via the downregulation of Keap1. Our study highlights the potential importance of the BRD4/Keap1/Nrf2 axis in the modulation of the oxidative stress response in trophoblast cells. Targeted inhibition of BRD4 may offer new opportunities for the development of innovative therapeutic approaches to treat preeclampsia.

Objective: To demonstrate the association between pre-pregnancy maternal overweight, obesity, and perinatal outcomes of singletons conceived by assisted reproductive technology (ART). Design: Retrospective cohort study from 2006 to 2015 data from a single ART center. Setting: Assisted Reproduction Center, Northwest Women's and Children's Hospital, Xi'an, Northwestern China. Patients: We included 7,818 women undergoing ART and their singleton infants. Interventions: None. Main Outcome Measure: The primary outcome measures were preterm birth (PTB), macrosomia, low birth weight, small for gestational age, and large for gestational age (LGA). Results: We experienced an increase in the risk of PTB, macrosomia, and LGA in overweight and obese groups compared with that in normal-weight groups [PTB: overweight vs. normal weight: odds ratio [OR] = 1.44, 95% CI: 1.18–1.75; obesity vs. normal weight: OR = 1.53, 95% CI: 1.04–2.25; macrosomia: overweight vs. normal weight: OR = 1.78, 95% CI: 1.48–2.14; obesity vs. normal weight: OR = 2.16, 95% CI: 1.52–3.06; LGA: overweight vs. normal weight: OR = 1.63, 95% CI: 1.39–1.90; obesity vs. normal weight: OR = 2.11, 95% CI: 1.57–2.83]. We observed a significant interaction between maternal BMI and fresh/frozen embryo transfer on PTB and LGA (P = 0.030; P = 0.030). Fresh embryo transfer significantly increased the effect of maternal BMI on LGA (fresh: OR = 1.14, 95% CI: 1.10–1.18; frozen: OR = 1.09, 95% CI: 1.04–1.13), and frozen embryo transfer increased the effect of maternal BMI on PTB (fresh: OR = 1.03, 95% CI: 0.99–1.08; frozen: OR = 1.09, 95% CI: 1.04–1.15). Conclusions: Pre-pregnancy maternal overweight and obesity were associated with higher risks of PTB, macrosomia, and LGA in ART-conceived singletons. These associations were affected by the timing of embryo transfer (fresh/frozen embryo transfer). Therefore, we recommend women before ART to maintain a normal BMI for the prevention of adverse perinatal outcomes.

Scope Hyperglycemia-induced cardiac fibrosis is one of the main causes of diabetic cardiomyopathy (DM). Chlorogenic acid (CGA) found in many foods has excellent hypoglycemic effectiveness, but it is not known whether CGA can improve DM by inhibiting cardiac fibrosis caused by hyperglycemia. Methods and results Type I diabetic mice were induced by streptozotocin, and after treatment with CGA for 12 weeks, cardiac functions and fibrosis were determined. CGA significantly attenuated hyperglycemia-induced cardiac fibrosis and improved cardiac functions. The mechanism of CGA on fibrotic inhibition was further studied by immunofluorescence, western blot and RNA interference technology in vivo and in vitro. The results showed CGA exerted its anti-fibrotic effects through activating the cyclic GMP/protein kinase G pathway (cGMP/PKG) to block hyperglycemia-induced nuclear translocation of p-Smad2/3, and then inhibiting pro-fibrotic gene expression in cardiac fibroblasts without depending on its hypoglycemic function. Moreover, the data also revealed that CGA increased cGMP level and activated PKG in cardiac fibroblasts by enhancing endothelial nitric oxide synthase activity and NO production. Conclusion Besides lowering blood glucose, CGA also has an independent ability to inhibit cardiac fibrosis. Therefore, long-term consumption of foods rich in CGA for diabetic patients will have great benefits to improve diabetic cardiomyopathy. This article is protected by copyright. All rights reserved.

SECTIONSPDFPDFTOOLS SHARE Summary The lack of neighbourhood aesthetics (e.g. public art and well‐maintained properties) may reduce walkability in the neighbourhood and increase the risk of childhood obesity. In this study, a literature search was conducted in the Cochrane Library, PubMed and Web of Science for articles published before January 1, 2019 to analyse the associations between neighbourhood aesthetics and weight‐related behaviours and outcomes among children and adolescents aged

To study the associations between heterogeneity of gestational diabetes mellitus (GDM) subtype/prepregnancy body mass index (pre-BMI) and large-for-gestational-age (LGA) infants of Chinese women.We performed a retrospective case-control study of 299 women with GDM and 204 women with normal glucose tolerance (NGT), using oral glucose tolerance test-based indices performed at 24-25 weeks of gestation. Women with GDM were classified into the following three physiologic subtypes: GDM with a predominant insulin-secretion defect (GDM-dysfunction), GDM with a predominant insulin-sensitivity defect (GDM-resistance), or GDM with both defects (GDM-mixed). We then used a binary logistic regression model to evaluate the potential associations of GDM subtypes and pre-BMI with newborn macrosomia or LGA.Women with GDM-resistance had a higher pre-BMI (P 0.001), whereas women in the GDM-dysfunction and GDM-mixed groups had pre-BMIs comparable to the NGT group. In the logistic regression model, women in the GDM-mixed group exhibited an increased risk of bearing newborns with macrosomia and LGA, and women in the GDM-dysfunction group tended to have newborns with LGA after adjusting for pre-BMI and other potential confounders. Women who were overweight or obese prepregnancy manifested an increased risk of having newborns with macrosomia and LGA relative to normal-weight women, regardless of whether values were unadjusted or adjusted for all potential confounders. There was no significant interaction between GDM subtype and pre-BMI for any of the studied outcomes.Heterogeneity of GDM (GDM-dysfunction and GDM-mixed) and prepregnancy overweight/obesity were independently associated with LGA in Chinese women. There was no significant interaction between GDM subtypes and pre-BMI for LGA.目的: 研究中国孕妇中, 妊娠期糖尿病(gestational diabetes mellitus, GDM)异质性分型及孕前体重指数分层(pre-pregnancy body mass index, pre-BMI)与大于胎龄儿(large-for-gestational-age, LGA)的关系。 方法: 我们进行了一项回顾性病例对照研究, 我们分析了299例GDM孕妇和204例正常糖耐量(normal glucose tolerance, NGT)孕妇的临床数据。诊断GDM依据妊娠第24-25周的口服糖耐量试验结果, 按照生理特征将GDM孕妇分为以下三种亚型: 以胰岛素分泌缺陷为主要特征的亚型(GDM-dysfunction, GDM-dys), 以胰岛素敏感性缺陷为主要特征的亚型(GDM-resistance, GDM-res), 或以上两种特征缺陷均具备的亚型(GDM-mixed)。使用二元logistic回归模型分析GDM亚型/pre-BMI与巨大儿或LGA的潜在关联。 结果: GDM-res组的pre-BMI较高(P 0.001), 而GDM-dys组和GDM-mixed组与NGT组的pre-BMI相当。在logistic回归模型中, GDM-mixed组生产巨大儿和LGA的风险增加, 而校正pre-BMI和其他潜在混杂因素后, GDM-dys组生产LGA的风险也增加。与正常孕前体重的孕妇相比, 无论是否调整潜在混在因素, 孕前超重/肥胖的孕妇生产巨大儿和LGA的风险均较高。同时, 本研究未发现GDM各亚型和各pre-BMI分组之间存在显著的交互作用。 结论: 中国GDM孕妇中, 依据异质性分组, GDM-dys/GDM-mixed亚型和孕前超重/肥胖与LGA独立相关。GDM各亚型与pre-BMI各分组之间对于LGA的影响没有显著的交互作用。.

Immune cell infiltration is an important indicator of whether tumor patients will benefit from immunotherapy. Gastric cancer is one of the most common tumors in the world, and new indicators of immunotherapy are urgently needed. The aim of this study was to construct ceRNA networks in gastric cancer with different degrees of immune cell infiltration. We analyzed the expression profiles of different gastric cancer with different degrees of immune cell infiltration retrieved from The Cancer Genome Atlas (TCGA) database and found differentially expressed lncRNAs, mRNAs, and miRNAs. A ceRNA regulatory network of gastric cancer with different degrees of immune cell infiltration was constructed using functional annotation, RNA‐RNA interaction prediction, correlation analysis, survival analysis, and other comprehensive bioinformatics methods. The interaction and correlation between ceRNAs were verified using experiments on tumor tissues and cell lines. Cell line experiments showed a potential RP11‐1094M14.8/miR‐1269a/CXCL9 axis that was consistent with the ceRNA theory. qRT‐PCR results showed that RP11‐1094M14.8 knockdown significantly reduced the expression of CXCL9, and RP11‐1094M14.8 overexpression had the opposite effect. The results of clinical analysis of gastric cancer samples showed that RP11‐1094M14.8 and CXCL9 were highly expressed in hot tumors, and CXCL9 was positively correlated with a better prognosis for patients. The constructed novel ceRNA network and the potential regulatory axis may provide a comprehensive understanding of the potential mechanisms of development in gastric cancer with different degrees of immune cell infiltration. The RP11‐1094M14.8/miR‐1269a/CXCL9 axis may serve as a potential immune‐therapeutic target for gastric cancer with different degrees of immune cell infiltration., Cell line experiments showed a potential RP11‐1094M14.8/miR‐1269a/CXCL9 axis that was consistent with the ceRNA theory. The RP11‐1094M14.8/miR‐1269a/CXCL9 axis may serve as a potential immune‐therapeutic target for gastric cancer with different degrees of immune cell infiltration

Gestational diabetes mellitus (GDM) is a condition in which a hormone made by the placenta prevents the body from using insulin effectively. It is important to find an effective treatment. A mouse model of GDM was used to testify the effects of astaxanthin on glucose tolerance and insulin sensitivity. Production of inflammatory cytokines, reactive oxygen species (ROS), and glucose transporter type 4 (GLUT4) translocation and insulin-related signaling were measured in the presence of astaxanthin both in vivo and in vitro. It was found that astaxanthin improved insulin sensitivity, glucose tolerance, and litter size of offspring and reduced birth weight of offspring and inflammation in GDM mouse. Moreover, astaxanthin increased GLUT4 translocating to membrane without altering its secretion/expression and glucose uptake and consumption in C2C12 skeletal muscle cells. Furthermore, ROS generation and insulin-related signaling inhibited by tumor necrosis factor α was restored by astaxanthin. It is concluded that astaxanthin has the potential to attenuate GDM symptoms by regulating inflammation and insulin resistance in skeletal muscle of pregnant mice. Our findings suggest that astaxanthin could be a promising and effective molecule to treat GDM.

Agrimonia pilosa (AP) and Rhus gall (RG) are traditional medicinal plants. The bioflavonoid composition standardized by HPLC analysis was named APRG64. Despite many studies reported to beneficial bioactivities of AP and RG, very limited range of toxicity tests have documented. So, we did experiment diversely on the toxicity tests of the substance APRG64. Genotoxicity (mammalian chromosomal aberration test, micronoucleus test) against APRG64, acute and sub-chronic toxicity test from rodent/non-rodent, and systemic safety pharmacology test were conducted. As a result of the test, genotoxicity against APRG64 was not observed. The NOAEL of rodents was confirmed as 2000 mg/kg/day and non-rodents was confirmed as 500 mg/kg/day. In addition, systemic safety pharmacological toxicity (effects on respiratory system, central nervous system, cardiovascular system) following administration of APRG64 was not observed. Finally, we accomplished ten potential toxicity tests and evaluated extensive safety of APRG64. Consequently, APRG64 may be a promising material for nutraceuticals and natural medicines.

ObjectiveTo compare the efficacy and safety of insulin detemir (IDet) versus neutral protamine Hagedorn (NPH) insulin used in pregnant women with diabetes.Research design and methodsA randomized study was conducted in diabetic pregnant women (n=240) (including 132 with pregestational diabetes and 108 with gestational diabetes). All patients were randomly divided into two groups: IDet group (n=120) treated with IDet plus short acting insulin Novolin-R before three meals (RRR–IDet plan), and NPH group treated with NPH plus Novolin-R before three meals (RRR–NPH plan). Patients were enrolled during 12–28 gestation weeks and followed up until delivery.ResultsBasal characteristics, such as age, enrollment gestational weeks, average HbA1c, fasting plasma glucose (FPG) and oral glucose tolerance test (OGTT) were similar between two groups. After 1 week of treatment, the FPG of IDet group were significantly lower than NPH group (pConclusionsFor the treatment of gestational diabetes, both RRR–IDet plan and RRR–NPH plan were reported to control blood glucose effectively. Compared with NPH, IDet could control blood glucose and reached the targets faster and more effectively, thus reducing the number of insulin injections and the incidence of hypoglycemia in pregnant women without increasing adverse birth outcomes. Therefore, for pregnant women with gestational diabetes, who require insulin therapy, IDet would be an ideal basal insulin being worthy of promotion in clinical settings.

BACKGROUND Low-dose aspirin has been the most widely studied preventive drug for preeclampsia. However, guidelines differ considerably from country to country regarding the prophylactic use of aspirin for preeclampsia. There is limited evidence from large trials to determine the effect of 100 mg of aspirin for preeclampsia screening in women with high-risk pregnancies, based on maternal risk factors, and to guide the use of low-dose aspirin in preeclampsia prevention in China. OBJECTIVE The Low-Dose Aspirin in the Prevention of Preeclampsia in China study was designed to evaluate the effect of 100 mg of aspirin in preventing preeclampsia among high-risk pregnant women screened with maternal risk factors in China, where preeclampsia is highly prevalent, and the status of low-dose aspirin supply is commonly suboptimal. STUDY DESIGN We conducted a multicenter randomized controlled trial at 13 tertiary hospitals from 11 provinces in China between 2016 and 2019. We assumed that the relative reduction in the incidence of preeclampsia was at least 20%, from 20% in the control group to 16% in the aspirin group. Therefore, the targeted recruitment number was 1000 participants. Women were randomly assigned to the aspirin or control group in a 1:1 allocation ratio. Statistical analyses were performed according to an intention-to-treat basis. The primary outcome was the incidence of preeclampsia, diagnosed along with a systolic blood pressure of ≥140 mm Hg or a diastolic blood pressure of ≥90 mm Hg after 20 weeks of gestation, with a previously normal blood pressure (systolic blood pressure of

The lack of precise therapies for stress-induced hypertension highlights the need to explore the process of blood pressure changes. Studies have shown that neuroinflammation in the central nervous system is associated with hypertension, although the mechanisms remain elusive. Microglia, are known to play dualistic protective and destructive roles, representing logical but challenging targets for improving stress-induced hypertension. Here, as a model, we used rats with stress-induced hypertension, and found that a switch from an immunoregulatory (M2) to a pro-inflammatory (M1) dominant response occurred in microglia during development of stress-induced hypertension. Administration of minocycline, which is commonly used to inhibit microglial M1 polarisation, attenuated the increase in activated microglia and M1 microglial markers expression in the hypothalamic paraventricular nucleus of rats with stress-induced hypertension. To shed further light on development of stress-induced hypertension, we examined changes in pro- and anti-inflammatory cytokines, and found increased expression of M2 microglial markers during early pathogenesis. Based on these results, we propose the possibility that M1/M2 microglia are related to development of stress-induced hypertension. Consequently, a target molecule that skews M2 polarisation of microglia may be a beneficial therapy for this disease.

Background Immunotherapy is important for the treatment of esophagogastric cancer. The purpose of this study is to compare the efficacy and safety of PD-(L)1 antibody, chemotherapy, and supportive treatment in the management of pretreated advanced esophagogastric cancer. Methods The randomized controlled trials were identified by searching electronic databases including PubMed, Cochrane Library and Embase database. The network meta-analysis (NMA) was carried out using software R 3.3.2. Main outcomes including overall survival (OS), progression-free survival (PFS), all grades and serious treatment-related adverse events (TRAEs) were extracted and analyzed. The ranking results for all outcomes were performed to identify the best treatments. Results Seven high-quality RCTs involving 1,891 patients were taken into analysis. Compared with supportive treatment, PD-(L)1 antibody and chemotherapy both had a significantly longer OS time. Chemotherapy could obvious improve PFS than supportive treatment, but it had more all grades and serious TRAEs than PD-(L)1 antibody and supportive treatment. No significant difference was found in other comparisons. The probabilities of rank plot showed that PD-(L)1 antibody was the best in the outcome of OS. Chemotherapy ranked first in PFS and ranked last in all grades and serious TRAEs. Conclusions According to our results, PD-(L)1 antibody had excellent survival benefits and tolerable TRAEs for pretreated advanced esophagogastric cancer. It might be a suitable potential choice, especially for patients with high PDL1 CPS or with gastroesophageal junction cancer.

Background This study was designed to research the potential function of lncRNA ANRIL in osteosarcoma (OS). Materials and methods Quantitative real-time PCR, cell counting kit-8, wound healing assay, Transwell assay, flow cytometric analysis, caspase activity analysis, and Western blot were carried out. Results ANRIL was remarkably upregulated in human OS tissues and cells, and knockdown of ANRIL significantly suppressed MG63 cell proliferation, migration, and invasion and promoted apoptosis. Moreover, our mechanistic research findings verified that ANRIL-influenced growth and apoptosis may be partly through regulation of caspase-3 and Bcl-2. Migration and invasion were influenced via ANRIL-mediated regulation of MTA1, TIMP-2, and E-cadherin. Conclusion Our finding demonstrates that ANRIL plays vital roles in OS growth and metastasis.

Integrating multifunctionality such as adhesiveness, stretchability, and self-healing ability on a single hydrogel has been a challenge and is a highly desired development for various applications including electronic skin, wound dressings, and wearable devices. In this study, a novel hydrogel was synthesized by incorporating polydopamine-coated talc (PDA-talc) nanoflakes into a polyacrylamide (PAM) hydrogel inspired by the natural mussel adhesive mechanism. Dopamine molecules were intercalated into talc and oxidized, which enhanced the dispersion of talc and preserved catechol groups in the hydrogel. The resulting dopamine-talc-PAM (DTPAM) hydrogel showed a remarkable stretchability, with over 1000% extension and a recovery rate over 99%. It also displayed strong adhesiveness to various substrates, including human skin, and the adhesion strength surpassed that of commercial double-sided tape and glue sticks, even as the hydrogel dehydrated over time. Moreover, the DTPAM hydrogel could rapidly self-heal and regain its mechanical properties without needing any external stimuli. It showed excellent biocompatibility and improved cell affinity to human fibroblasts compared to the PAM hydrogel. When used as a strain sensor, the DTPAM hydrogel showed high sensitivity, with a gauge factor of 0.693 at 1000% strain, and was capable of monitoring various human motions such as the bending of a finger, knee, or elbow and taking a deep breath. Therefore, this hydrogel displays favorable attributes and is highly suitable for use in human-friendly biological devices.

Objective Chromosome aberrations are generally considered as one of the most substantial causative factors contributing to spontaneous miscarriages. Cytogenetic analyses like G-banded karyotype and chromosomal microarray analyses are often performed to further investigate the chromosome status of a miscarried fetus. Study design Here, we describe a novel method, AnnoCNV, to detect DNA copy number variations (CNVs) using low coverage whole genome sequencing (WGS). We investigated the overall frequency of chromosomal abnormalities in 149 miscarriage specimens using AnnoCNV. Results Among 149 fetal miscarriage samples, more than two fifths of them (42.95%, 64) carried at least one chromosomal abnormality, and a subset (40) was identified as autosomal trisomy which account for 26.84% of all samples. We have also developed a robust algorithm in AnnoCNV, which is able to differentiate specifically karyotype 69,XXY from sex chromosomal aneuploidy 45,X, and to identify 45,X/46,XX mosaicism. Lastly, across the whole genome AnnoCNV identifies CNVs, which are associated with both reported symptoms and unknown clinical conditions. Conclusion This cost-effective strategy reveals genome wide discovery of chromosome aberrations at higher resolution, which are consistent with parallel investigation conducted by SNP based assay.

The performance of a semiconductor electronic or photonic device depends greatly on the properties of the interface. In a typical perovskite solar cell (PSC), the interface between electron transport layer (ETL) and perovskites is found to significantly influence the power conversion efficiency (PCE). Herein, Ultraviolet-ozone (UVO) treatment, a technique commonly used to clean a device substrate, is applied on ETL, specially, mesoporous/compact TiO2 layer. This treatment increases the conductivity of ETL and removes the residual organics at the surface. Consequently, an improved interface between mesoporous TiO2 and perovskite is achieved to enhance the performance of PSC. For example, the fill factor (FF) increases by ∼13%, the short-circuit current density (Jsc) and open-circuit voltage (Voc) increase by ∼2%, and the PCE finally enhances by ∼20% with 15 min of UVO treatment. With this method, the PCE of the best cell reaches to 20.43% under the illumination of AM 1.5 (100 mW cm−2) simulated sunlight.

Sophora moorcroftiana (S. moorcroftiana) is an endemic leguminous dwarf shrub in Tibet, China. Decoctions of the seeds have been used in Chinese folk medicine for dephlogistication, detoxication, and infectious diseases. The present study aimed to investigate the constituent and biological effects of polysaccharides from S. moorcroftiana seeds in Caenorhabditis elegans (C. elegans). Polysaccharides from S. moorcroftiana seeds (SMpol) were extracted with 60% ethanol and constituent was analyzed by GC-MS. SMpol was composed of glucose, galactose and inositol in the molar ratio of 35.7 : 1.3 : 17.0. Synchronized worms were treated with SMpol and then lifespan, motility, reproduction, stress resistance and antimicrobial activity were examined. Compared with the control group, the lifespan was increased to the average of 27.3 days and the number of laying eggs showed a 1.3-fold increase in nematodes treated with SMpol (4 mg·mL-1). In SMpol (4 mg·mL-1) treated worms, there was a 1.1-fold increase in 24-h survival of acute heat stress and a 1.6-fold increase in 2-h survival of oxidative stress The colonization of the bacteria in the SMpol treated nematode was significantly lower than that of the untreated group by 68.3%. In vivo studies showed SMpol significantly extended the life span, improved reproduction, increased stress resistance and antimicrobial capacity of C. elegans. In conclusion, those results indicated that the polysaccharides from S. moorcroftiana seeds were involved in a variety of biological activities leading to its modulatory effects on C. elegans which may be developed as a natural supplement agent.