ER-ß accelerates the process of primary osteoporosis by promoting VEGFA-mediated apoptosis of osteoblasts.

Primary osteoporosis (POP) is a widespread and severe disorder of bone metabolism characterized by reduced bone mass and destruction of bone structure, frequently inducing fracture risk and imposing a heavy economic burden on public life. The development of POP partially revolves around the estrogen receptor ß (ER-ß), one of the major mediator receptors of estrogen that influences apoptosis in a range of cells. We performed KEGG and GO analysis by mining the transcriptomic dataset of POP samples showing significant enrichment of differentially expressed genes (DEGs) in multiple apoptosis-related pathways. The results of the Spearman correlation analysis and Protein-Protein Interaction (PPI) Networks screening of hub genes indicated that vascular endothelial growth factor A (VEGFA) may be a key target of ER-ß in controlling osteoblast apoptosis. Further, we carried out high-throughput sequencing of ESR2-silenced MC3T3-E1 cells and noticed a substantial suppression in VEGFA expression and all apoptosis-related pathways. In addition, we determined the cell cycle and apoptosis by constructing a VEGFA-silenced cell model utilizing flow cytometry (FCM), and the results showed that ER-ß could regulate the osteoblast cycle and thus promote osteoblast apoptosis by promoting VEGFA expression. And Western blot results showed that apoptosis was most likely realized through the regulation of downstream apoptosis markers c-JUN (c-Jun N-terminal kinase, JNK) and GADD45G (Growth Arrest and DNA Damage-Inducible Protein 45 gamma). The effects of ESR2 and VEGFA on the proliferation of osteoblasts were lastly assessed using the cell counting kit- 8 (CCK-8) assay. In conclusion, this study identifies that the roles of ER-ß in the regulation of osteoblast apoptosis are closely related to VEGFA and provides a new target for POP treatment.

Angiotensin-converting enzyme 2 identifies immuno-hot tumors suggesting angiotensin-(1-7) as a sensitizer for chemotherapy and immunotherapy in breast cancer.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is known as a tumor suppressor and lowly expressed in most cancers. The expression pattern and role of ACE2 in breast cancer (BC) have not been deeply elucidated. METHODS: A systematic pan-cancer analysis was conducted to assess the expression pattern and immunological role of ACE2 based on RNA-sequencing (RNA-seq) data downloaded from The Cancer Genome Atlas (TCGA). The correlation of ACE2 expression and immunological characteristics in the BC tumor microenvironment (TME) was evaluated. The role of ACE2 in predicting the response to therapeutic options was estimated. Moreover, the pharmacodynamic effect of angiotensin-(1-7) (Ang-1-7), the product of ACE2, on chemotherapy and immunotherapy was evaluated on the BALB/c mouse BC model. In addition, the plasma samples from BC patients receiving neoadjuvant chemotherapy were collected and subjected to the correlation analysis of the expression level of Ang-1-7 and the response to neoadjuvant chemotherapy. RESULTS: ACE2 was lowly expressed in BC tissues compared with that in adjacent tissues. Interestingly, ACE2 was shown the highest correlation with immunomodulators, tumor-infiltrating immune cells (TIICs), cancer immunity cycles, immune checkpoints, and tumor mutation burden (TMB) in BC. In addition, a high level of ACE2 indicated a low response to endocrine therapy and a high response to chemotherapy, anti-ERBB therapy, antiangiogenic therapy and immunotherapy. In the mouse model, Ang-1-7 sensitized mouse BC to the chemotherapy and anti-PD-1 immunotherapy, which revealed its significant anti-tumor effect. Moreover, a high plasma level of Ang-1-7 was associated with a better response to neoadjuvant chemotherapy. CONCLUSIONS: ACE2 identifies immuno-hot tumors in BC, and its enzymatic product Ang-1-7 sensitizes BC to the chemotherapy and immunotherapy by remodeling the TME.

Yang-warming method in the treatment of diabetic peripheral neuropathy: an updated systematic review and meta-analysis.

BACKGROUND: Various studies have suggested the effectiveness of Chinese medicine in the treatment of diabetic peripheral neuropathy (DPN). There are several principles and methods in Chinese medicine for the treatment of DPN and yang-warming method is one of them. The purpose of this meta-analysis was to review the effectiveness and safety of yang-warming method using yang-warming Chinese medicine (YCM) in the treatment of DPN. METHODS: A computer-based search of the articles from January 2001 to April 2016 with Chinese and English databases such as CNKI, CBM, Wanfang, VIP, Medline, Embase and Cochrane central register of controlled trials as well as manual search of the related articles was conducted. Randomized Controlled Trials (RCTs) comparing yang-warming Chinese medicines with western medicines in the treatment of DPN were considered for the study. The outcome measures were change in the sensory or motor nerve conduction velocity, total efficacy rate evaluated by clinical symptoms improvement, and adverse events. Two authors independently assessed the methodological quality of the included articles using Jadad scale and the twelve criteria recommended by Cochrane Back Review Group. Data were analyzed using RevMan 5.3 software provided by Cochrane collaboration. RESULTS: A total of 25 articles were taken for the study. Meta-analysis results showed that yang-warming Chinese medicines used in the formula alone or in combination with western medicines improved the nerve conduction velocity (NCV) in comparison to western medicines alone (p < 0.001). There was also a significant difference in the total efficacy rate between the two groups (p < 0.001). Most of the included studies did not clearly report the adverse events. CONCLUSIONS: Yang-warming Chinese medicines alone or in combination with western medicines were apparently better than conventional western medicines in the treatment of DPN. Because of the poor quality of the reported works that were available for the present meta-analysis, it is earlier to claim the superiority of yang-warming method using YCM to western medicines for the treatment of DPN. To support these early findings, further standardized and rigorous RCTs are required.

Vitamin D3 attenuates autoimmune thyroiditis by regulating Th17/Treg cell differentiation via YAP/JAK1/STAT1 axis.

BACKGROUND: Autoimmune thyroiditis (AITD) is an organ-specific autoimmune disease. Substantial evidence suggests that Vitamin D (VitD) deficiency is closely associated with an increased risk of AITD. However, the effects of VitD3 on immune cells, especially Th17/Treg cell subsets, and the underlying molecular mechanism in AITD have not yet been investigated. METHODS: An experimental autoimmune thyroiditis (EAT) mouse model was established with a high-iodine diet. After 8 weeks, thyroid injury was assessed using hematoxylin and eosin (H&E) staining. ELISA was employed to measure serum levels of thyroxine (T3 and T4), thyroid autoimmune antibodies (Tg-Ab and TPO-Ab), and inflammatory cytokines. Flow cytometry and multiplex fluorescence immunohistochemical (mIHC) assays were used to analyze Th17/Treg cell subsets. The CCK-8 and flow cytometry assays were used to determine cell viability and apoptosis. RESULTS: Administration of VitD3 reduced thyroid follicle destruction, decreased lymphocyte infiltration, and lowered T3, T4, Tg-Ab, and TPO-Ab serum levels in EAT mice. VitD3 treatment also reduced the frequency of Th17 cells while promoting the Treg cell subset both in the thyroid tissue and in the splenocytes cultured in vitro. Furthermore, VitD3 administration suppressed the production of inflammatory cytokines in EAT mice. VitD3 was also found to regulate Treg cells' differentiation, viability, and apoptosis. Mechanistically, we discovered that VitD3 treatment upregulated YAP expression and activated the JAK/STAT pathway. Rescue assays confirmed that depletion of YAP counteracted the effects of VitD3 on Treg cell differentiation and function. CONCLUSION: Vitamin D3 attenuates AITD by modulating Th17/Treg cell balance via regulating the YAP/JAK1/STAT1 axis.

Cross-Cultural Generalizability of the First Year Inventory for Early ASD Screening in China.

The First Year Inventory (FYI) is a parent report screening measure, aimed at identifying the risk of autism spectrum disorder (ASD) in 12-month-old infants. This study aimed to investigate the utility of FYI within the Chinese community and develop a short version, encompassing both a low-risk sample and a high-risk sample comprising infants with older siblings diagnosed with ASD. Parents of 53 high-risk (HR) infants and 519 low-risk (LR) infants, aged 11 to 13 months, were recruited. After comparing response distributions across Chinese and American samples, a new factorial structure was developed according to the factor analyses. The construct validity and internal consistency of the two FYI versions were examined. The implementation of FYI in the HR sample was also assessed. Noteworthy disparities in response distribution were observed between the Chinese and American samples. Both FYI 2.0 and the FYI short version demonstrated moderate construct validity and internal consistency, with the FYI short version exhibiting better predictive ability in the HR sample. Significant lower risk scores was observed in the HR sample compared to the LR sample. These findings substantiate the applicability and validity of the Chinese short version of FYI. Future research should include follow-up assessments with the Chinese sample to evaluate cutoff scores, considering the cutoff between sensitivity and specificity and the sample?s characteristics.

Social Brain Network of Children with Autism Spectrum Disorder: Characterization of Functional Connectivity and Potential Association with Stereotyped Behavior.

Objective: To identify patterns of social dysfunction in adolescents with autism spectrum disorder (ASD), study the potential linkage between social brain networks and stereotyped behavior, and further explore potential targets of non-invasive nerve stimulation to improve social disorders. Methods: Voxel-wise and ROI-wise analysis methods were adopted to explore abnormalities in the functional activity of social-related regions of the brain. Then, we analyzed the relationships between clinical variables and the statistical indicators of social-related brain regions. Results: Compared with the typically developing group, the functional connectivity strength of social-related brain regions with the precentral gyrus, postcentral gyrus, supplementary motor area, paracentral lobule, median cingulum, and paracingulum gyri was significantly weakened in the ASD group (all p < 0. 01). The functional connectivity was negatively correlated with communication, social interaction, communication + social interaction, and the total score of the ADOS scale (r = -0.38, -0.39, -0.40, and -0.3, respectively; all p < 0.01), with social awareness, social cognition, social communication, social motivation, autistic mannerisms, and the total score of the SRS scale (r = -0.32, -0.32, -0.40, -0.30, -0.28, and -0.27, respectively; all p < 0.01), and with the total score of SCQ (r = -0.27, p < 0.01). In addition, significant intergroup differences in clustering coefficients and betweenness centrality were seen across multiple brain regions in the ASD group. Conclusions: The functional connectivity between social-related brain regions and many other brain regions was significantly weakened compared to the typically developing group, and it was negatively correlated with social disorders. Social network dysfunction seems to be related to stereotyped behavior. Therefore, these social-related brain regions may be taken as potential stimulation targets of non-invasive nerve stimulation to improve social dysfunction in children with ASD in the future.

Changes of heavy metal concentrations in farmland soils affected by non-ferrous metal smelting in China: A meta-analysis.

Long-term human smelting activities have resulted in substantial heavy metals (HMs) pollution of farmland soils around smelting sites, and the safety of farmland products is critical for human health. The current study focuses on HMs in farmland soils surrounding a single smelter, therefore the impact of smelting on a national scale needs to be investigated further. This study was based on 116 papers and 1143 sets of relevant data for meta-analysis, and a hierarchical mixed-effects model was used to quantify the changes of HMs concentrations in farmland soils affected by non-ferrous metal smelting on a national scale, as well as their relationships with relevant explanatory variables in China. Results showed that: (i) non-ferrous metal smelting substantially increased farmland soils HMs concentrations (323%), with each HM concentration increasing in the following order: Cd (2753%) > Pb (562%) > Hg (455%) > Zn (228%) > Cu (158%) > As (107%) > Ni (52%); (ii) the highest increase of HMs in vegetable fields (361%), but not significant in comparison to other farmland categories, and the increase of Pb, Zn, Cu and As concentrations were significantly different in different types of smelting areas; (iii) the increase of Hg was significantly higher in the northern region than in the southern region, and the opposite increase of Cu; (iv) the soil depth from 0 to 40 cm was significantly affected by smelting, and the increase of multiple HMs were significantly positively correlated with soil pH and negatively correlated with distance; (v) the other explanatory variables (farmland category and soil organic matter) were not significantly related to the effect of smelting. The results can provide some reference for protecting and restoring farmland soils around smelting areas.

Based on mRNA Sequencing Techniques to Explore the Molecular Mechanism of Buzhong Yiqi Decoction for Autoimmune Thyroiditis.

OBJECTIVE: Autoimmune diseases (AD) account for a high percentage of the population. One of the most prevalent is autoimmune thyroiditis (AIT). However, the therapeutic effects of Buzhong Yiqi (BZYQ) decoction on AIT have not been studied yet. The majority of the present study was conducted on NOD.H-2h4 mice in an attempt to ascertain the therapeutic effects of BZYQ decoction on AIT. METHODS: The 0.05% sodium iodide water (NaI)-induced AIT mice model was established. A total of nine NOD.H-2h4 mice were randomly divided into three groups: the normal group provided with regular water, the model group drinking freely 0.05% NaI, and the treatment group treated with BZYQ decoction (9.56 g/kg) after NaI supplementation (NaI + BZYQ). BZYQ decoction was administered orally once daily for eight weeks. The thyroid histopathology test was used to measure the severity of lymphocytic infiltration. An enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of anti-thyroglobulin antibody (TgAb), interleukin (IL)-1ß, IL-6, and IL-17. The Illumina HiSeq X sequencing platform was utilized to analyze the thyroid tissue by mRNA expression profiles. Bioinformatics analysis was used to investigate the biological function of the differentially expressed mRNAs. In addition, the expression of Carbonyl Reductase 1 (CBR1), 6-Pyruvoyltetrahydropterin Synthase (PTS), Major Histocompatibility Complex, Class II (H2-EB1), Interleukin 23 Subunit Alpha (IL-23A), Interleukin 6 Receptor (IL-6RA), and Janus Kinase 1 (JAK1) was measured by quantitative real-time PCR (qRT-PCR). RESULTS: The treatment group exhibited significantly lower rates of thyroiditis and lymphocyte infiltration compared to the model group. Serum levels of TgAb, IL-1ß, IL-6, and IL-17 were significantly higher in the model group, but they fell dramatically after BZYQ decoction administration. According to our results, 495 genes showed differential expression in the model group compared to the control group. Six hundred twenty-five genes were significantly deregulated in the treatment group compared to the model group. Bioinformatic analysis showed that most mRNAs were associated with immune-inflammatory responses and were involved in multiple signaling pathways, including folate biosynthesis and the Th17 cell differentiation pathway. CBR1, PTS, H2-EB1, IL23A, IL-6RA and JAK1 mRNA participated in folate biosynthesis and the Th17 cell differentiation pathway. The qRT-PCR analysis confirmed that the above mRNAs were regulated in the model group compared to the treatment group Conclusion: The results of this investigation have revealed novel insights into the molecular mechanism of action of BZYQ decoction against AIT. The mechanism may be partially attributed to the regulation of mRNA expression and pathways.

Possible molecular exploration of herbal pair Haizao-Kunbu in the treatment of Graves' disease by network pharmacology, molecular docking, and molecular dynamic analysis.

Objective: To promote the development and therapeutic application of new medications, it is crucial to conduct a thorough investigation into the mechanism by which the traditional Chinese herb pair of Haizao-Kunbu (HK) treats Graves' disease (GD). Materials and methods: Chemical ingredients of HK, putative target genes, and GD-associated genes were retrieved from online public databases. Using Cytoscape 3.9.1, a compound-gene target network was established to explore the association between prosperous ingredients and targets. STRING, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway analyses visualized core targets and disease pathways. Additionally, we conducted a refined analysis of the binding interactions between active ingredients and their respective targets. To visualize these findings, we employed precise molecular docking techniques. Furthermore, we carried out molecular dynamics simulations to gain insights into the formation of more tightly bound complexes. Results: We found that there were nine key active ingredients in HK, which mainly acted on 21 targets. These targets primarily regulated several biological processes such as cell population proliferation, protein phosphorylation, and regulation of kinase activity, and acted on PI3K-AKT and MAPK pathways to treat GD. Analysis of the molecular interaction simulation under computer technology revealed that the key targets exhibited strong binding activity to active ingredients, and Fucosterol-AKT1 and Isofucosterol-AKT1 complexes were highly stable in humans. Conclusion: This study demonstrates that HK exerts therapeutic effects on GD in a multi-component, multi-target, and multi-pathway manner by regulating cell proliferation, differentiation, inflammation, and immunomodulatory-related targets. This study provides a theoretical foundation for further investigation into GD.

High definition transcranial direct current stimulation of the Cz improves social dysfunction in children with autism spectrum disorder: A randomized, sham, controlled study.

The purpose of this study was to determine the effect of the Cz of high-definition 5-channel tDCS (HD-tDCS) on social function in 4-12 years-old children with autism spectrum disorder (ASD). This study was a randomized, double-blind, pseudo-controlled trial in which 45 ASD children were recruited and divided into three groups with sex, age, and rehabilitation treatment as control variables. Each group of 15 children with ASD was randomly administered active HD-tDCS with the Cz as the central anode, active HD-tDCS with the left dorsolateral prefrontal cortex (F3) as the central anode, and sham HD-tDCS with the Cz as the central anode with 14 daily sessions in 3 weeks. The Social Responsiveness Scale Chinese Version (SRS-Chinese Version) was compared 1 week after stimulation with values recorded 1 week prior to stimulation. At the end of treatment, both the anodal Cz and anodal left DLFPC tDCS decreased the measures of SRS-Chinese Version. The total score of SRS-Chinese Version decreased by 13.08%, social cognition decreased by 18.33%, and social communication decreased by 10.79%, which were significantly improved over the Cz central anode active stimulation group, especially in children with young age, and middle and low function. There was no significant change in the total score and subscale score of SRS-Chinese Version over the Cz central anode sham stimulation group. In the F3 central anode active stimulation group, the total score of SRS-Chinese Version decreased by 13%, autistic behavior decreased by 19.39%, and social communication decreased by 14.39%, which were all significantly improved. However, there was no significant difference in effect between the Cz and left DLPFC stimulation conditions. HD-tDCS of the Cz central anode may be an effective treatment for social dysfunction in children with ASD.

[Study on mechanism of traditional Chinese medicines reducing phlegm and resolving masses in treatment of goiter].

OBJECTIVE: To discuss the mechanism of traditional Chinese medicines reducing phlegm and resolving masses in treatment of iodine deficiency-induced goiter by observing the expression of growth factors and the balance-regulating mechanism of proliferation and apoptosis. METHOD: 180 four-week-old Wistar rats were selected to establish the iodine deficiency model. After the modeling, the rats were randomly divided into six groups: the normal control group, the model control group, the iodine group, the phlegm compound group, the L-T4 group and the phlegm compound and L-T4 group. At the 21st day and 77th day after administration, 15 rats in each group were killed to collect specimens. Doses were calculated and adjusted according to body surface area and body weight. TT3, TT4 radioimmunoassay, TSH, immunoradiometric method were adopted. Fas, FasL and PCNA protein expressions are detected using immunohistochemical methods. RESULT: Compared with the normal group and the model group, the expressions of fas and FasL in the phlegm Group significantly increased, the expressions of fas and FasL in the phlegm and L-T4 group were also increased significantly. The expression of fas in the L-T4 Group was significantly lower than that of the L-T4 group and the phlegm compound and L-T4 group. Compared with the normal group, the expression of PCNA of the phlegm group and the phlegm and L-T4 group was significantly lower. Compared with the model group, the expression of PCNA of the iodine group, the phlegm groups and the phlegm and L-T4 group were significantly lower. Compared with the normal group, the expression of VEGF in the iodine group significantly decreased after treatment. Compared with the iodine group, the expression of VEGF in the phlegm group and the L-T4 group significantly reduced. Compared with the normal group, the expression of TGF-beta1 in the model group and the phlegm group significantly increased. Compared with model group, the expression of TGF-beta1 in the iodine group significantly reduced. Compared with the phlegm group, the expression of TGF-beta1 in the phlegm compound and L-T4 group was significantly reduced. CONCLUSION: Traditional Chinese medicines reducing phlegm and resolving masses can completely recover goiter by promoting apoptosis of thyroid cells, inhibiting their proliferation and the expression of growth factors and enhancing the expression of TGF-beta, without causing injury on thyroid cells.

Relationship of Soluble Klotho and Early Stage of Diabetic Nephropathy: A Systematic Review and Meta-Analysis.

Background: Diabetic nephropathy (DN) is a chronic microvascular complication caused by long-term hyperglycemia in patients with diabetes and an important cause of end-stage renal disease. Although some studies have shown that soluble Klotho(sKlotho) levels of patients with DN are lower than those without DN, in the early stage of patients with DN with normal renal function and albuminuria, the change in sKlotho is still controversial. Aim: This meta-analysis was conducted to statistically evaluate sKlotho levels in patients with DN. Methods: We searched the following electronic databases: Web of Science, Embase, PubMed, Google Scholar, and China National Knowledge Infrastructure (CNKI). The following search terms were used for the title or abstract: "diabetic kidney disease", "diabetic nephropathy", OR "DN" in combination with "Klotho". The meta-analysis results were presented as standardized mean differences (SMDs) with corresponding 95% confidence intervals (CIs). Results: Fourteen articles were included in the meta-analysis. In our meta-analysis, we found that the sKlotho level in patients with DN was significantly lower than that in patients without DN (SMD: -1.52, 95% CI [-2.24, -0.80]), and it was also significantly lower in the early stage of DN (SMD: -1.65, 95% CI [-2.60, -0.70]). Conclusions: This systematic review was the first to evaluate the relationship between sKlotho levels and DN. The sKlotho level was significantly lower in the early stages of DN, indicating that sKlotho might be a new biomarker of DN in the future.

Molecular mechanism of Sishen pills in the treatment of diarrheal diabetic enteropathy based on network pharmacology.

This study aimed to explore the effectiveness and safety of Sishen pills for the treatment of diarrheal diabetic enteropathy (DDE). The Traditional Chinese Medicine (TCM) Systems Pharmacology and BATMAN-TCM databases were used to determine the chemical composition of Sishen pills and thus predict information on protein targets. We searched for potential targets of DDE in the GeneCards, DrugBank, Therapeutic Target (TTD), and DisGeNET databases. Using the intersection of the drug and disease targets, protein-protein interaction (PPI) networks and molecular interaction modules were constructed, and key targets were screened. The intersecting gene targets were imported into the Metascape database to conduct Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The core targets and active ingredients were then docked at the molecular level. Sishen pills contain 70 active ingredients, 463 targets, and 566 disease targets. A module analysis of the targets revealed that the module was mainly related to adrenergic receptor activity, the adenosine phosphate kinase signaling pathway, and the G protein-coupled receptor signaling pathway. The GO and KEGG pathway enrichment results indicated that the protein genes regulated by Sishen pills were mainly enriched in the response to lipopolysaccharides, the AMPK signaling pathway, the JAK-STAT signaling pathway, and other signaling pathways. The molecular docking results showed that the core active compounds exhibited good binding activity with the predicted targets. Sishen pills can regulate the immune function of the body through anti-inflammatory and antibacterial effects for the treatment of DDE.

Therapeutic effects and mechanisms of N-(9,10-anthraquinone-2-ylcarbonyl) xanthine oxidase inhibitors on hyperuricemia.

Objective: To observe the antioxidative effects of N-(9,10-anthraquinone-2-ylcarbonyl) xanthine oxidase inhibitors (NAY) in vitro and in vivo models of hyperuricemia and explore the mechanism. Methods: A classical experimental method of acute toxicity and a chronic toxicity test were used to compare the toxic effects of different doses of NAY in mice. The hyperuricemia mouse model was established by gavage of potassium oxonate in vivo. After treatment with different doses of NAY (low dose: 10 mg/kg, medium dose: 20 mg/kg, and high dose: 40 mg/kg) and allopurinol (positive drug, 10 mg/kg), observe the levels of uric acid (UA), creatinine (CRE), and urea nitrogen (BUN) in urine and serum, respectively, and detect the activities of xanthine oxidase in the liver. The hyperuricemia cell model was induced by adenosine and xanthine oxidase in vitro. The cells were given different doses of NAY (50, 100, and 200 µmol/L) and allopurinol (100 µmol/L). Then the culture supernatant UA level of the medium was measured. The next step was to detect the xanthine oxidase activity in the liver and AML12 cells, and the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammatory factors in the kidney and serum of mice. Western blot was used to detect xanthine oxidase protein expression in mouse liver tissue and AML12 cells, ASC, Caspase-1, NLRP3, GLUT9, OAT1, and OAT3 protein expression in mouse kidney tissue and HK-2 cells. Hematoxylin-eosin staining was used to stain the liver and kidney tissues of mice and observe the tissue lesions. Results: NAY had little effect on blood routine and biochemical indexes of mice, but significantly reduced the serum UA level. NAY significantly reduced the level of UA in hyperuricemia mice and cells by inhibiting xanthine oxidase activity and reduced the levels of TNF-α, IL-6, and other inflammatory factors in serum and kidney of mice. NAY can inhibit inflammation by inhibiting the NLRP3 pathway. In addition, NAY can downregulate GLUT9 protein expression and upregulate OAT1 and OAT3 protein expression to reduce the UA level by promoting UA excretion and inhibiting UA reabsorption. Conclusion: These findings suggested that NAY produced dual hypouricemic actions. On the one hand, it can inhibit the formation of UA by inhibiting xanthine oxidase inhibitors activity, and on the other hand, it can promote the excretion of UA by regulating the UA transporter. It provides new ideas for the development of hyperuricemia drugs in the future.

[Alterations in reactive oxygen species and dimethylarginine dimethylaminohydrolase-asymmetric dimethyl-arginine system in the process of endothelial cell senescence induced by high glucose].

OBJECTIVE: To investigate the changes in reactive oxygen species (ROS) and dimethyl- arginine dimethylaminohydrolase-asymmetric dimethylarginine (DDAH-ADMA) system in the process of endothelial cell senescence after exposure to high glucose. METHODS: The human umbilical vein endothelial cells (HUVECs) were cultured with different concentrations of glucose, e.g. 5.5 mmol/L (normal level), and high levels as 11.0, 22.0 and 33.0 mmol/L, for 48 hours, respectively. Subsequently, SA-ß-gal staining was used to evaluate senescence of cells. Telomerase activity was detected by polymerase chain reaction-enzyme linked immunosorbent assay (PCR-ELISA). The intracellular ROS level was measured by flow cytometry. The ADMA concentration and DDAH activity were determined with high-performance liquid chromatography. RESULTS: Compared with normal glucose concentration group, after the endothelial cells were treated with high glucose concentration (11.0-33.0 mmol/L) for 48 hours, the number of SA-ß-gal positive cells was increased significantly [(7.00±1.73)%, (12.67±2.03)%, (16.00±2.26)% vs. (4.00±1.33)%, P>0.05, P<0.05, P<0.05] and the telomerase activity was inhibited dramatically [(91.32±4.01)%, (78.44±3.78)%, (56.04±3.35)% vs. 100%, all P<0.05]. The ROS level (mfi) was increased in all high glucose groups (159.84±27.52, 188.99±18.77, 244.56±20.96 vs.117.11±18.76, P<0.05 or P<0.01). At the same time, the ADMA (µmol/L) production was increas ed (0.78±0.14, 0.88±0.18, 1.08±0.15 vs. 0.70±0.12, P>0.05, P<0.05, P<0.05), and DDAH activity was decreased [(91.32±4.01)%, (78.44±3.78)%, (56.04±3.35)% vs.100%, all P<0.05]. CONCLUSION: High glucose can accelerate endothelial cells senescence in dose-dependent manner and the underlying mechanism may be related to an increased oxidative stress and change in DDAH-ADMA system.

Biological role of heparan sulfate in osteogenesis: A review.

Heparan sulfate (HS) is extensively expressed in cells, for example, cell membrane and extracellular matrix of most mammalian cells and tissues, playing a key role in the growth and development of life by maintaining homeostasis and implicating in the etiology and diseases. Recent studies have revealed that HS is involved in osteogenesis via coordinating multiple signaling pathways. The potential effect of HS on osteogenesis is a complicated and delicate biological process, which involves the participation of osteocytes, chondrocytes, osteoblasts, osteoclasts and a variety of cytokines. In this review, we summarized the structural and functional characteristics of HS and highlighted the molecular mechanism of HS in bone metabolism to provide novel research perspectives for the further medical research.

Control and function of the homeostatic sleep response by adenosine A1 receptors.

During sleep, the mammalian CNS undergoes widespread, synchronized slow-wave activity (SWA) that directly varies with previous waking duration (Borbély, 1982; Dijk et al., 1990). When sleep is restricted, an enhanced SWA response follows in the next sleep period. The enhancement of SWA is associated with improved cognitive performance (Huber et al., 2004), but it is unclear either how the SWA is enhanced or whether SWA is needed to maintain normal cognitive performance. A conditional, CNS knock-out of the adenosine receptor, AdoA(1)R gene, shows selective attenuation of the SWA rebound response to restricted sleep, but sleep duration is not affected. During sleep restriction, wild phenotype animals express a rebound SWA response and maintain cognitive performance in a working memory task. However, the knock-out animals not only show a reduced rebound SWA response but they also fail to maintain normal cognitive function, although this function is normal when sleep is not restricted. Thus, AdoA(1)R activation is needed for normal rebound SWA, and when the SWA rebound is reduced, there is a failure to maintain working memory function, suggesting a functional role for SWA homeostasis.

Effect of iodine intake on thyroid diseases in China.

BACKGROUND: Iodine is an essential component of thyroid hormones; either low or high intake may lead to thyroid disease. We observed an increase in the prevalence of overt hypothyroidism, subclinical hypothyroidism, and autoimmune thyroiditis with increasing iodine intake in China in cohorts from three regions with different levels of iodine intake: mildly deficient (median urinary iodine excretion, 84 microg per liter), more than adequate (median, 243 microg per liter), and excessive (median, 651 microg per liter). Participants enrolled in a baseline study in 1999, and during the five-year follow-up through 2004, we examined the effect of regional differences in iodine intake on the incidence of thyroid disease. METHODS: Of the 3761 unselected subjects who were enrolled at baseline, 3018 (80.2 percent) participated in this follow-up study. Levels of thyroid hormones and thyroid autoantibodies in serum, and iodine in urine, were measured and B-mode ultrasonography of the thyroid was performed at baseline and follow-up. RESULTS: Among subjects with mildly deficient iodine intake, those with more than adequate intake, and those with excessive intake, the cumulative incidence of overt hypothyroidism was 0.2 percent, 0.5 percent, and 0.3 percent, respectively; that of subclinical hypothyroidism, 0.2 percent, 2.6 percent, and 2.9 percent, respectively; and that of autoimmune thyroiditis, 0.2 percent, 1.0 percent, and 1.3 percent, respectively. Among subjects with euthyroidism and antithyroid antibodies at baseline, the five-year incidence of elevated serum thyrotropin levels was greater among those with more than adequate or excessive iodine intake than among those with mildly deficient iodine intake. A baseline serum thyrotropin level of 1.0 to 1.9 mIU per liter was associated with the lowest subsequent incidence of abnormal thyroid function. CONCLUSIONS: More than adequate or excessive iodine intake may lead to hypothyroidism and autoimmune thyroiditis.

Efficacy and safety of tripterygium glycosides for Graves ophthalmopathy: A systematic review and meta-analysis.

BACKGROUND: Graves ophthalmopathy (GO) is one of the remaining enigmas in thyroidology. Glucocorticoids (GCs) are strongly recommended but their effects are not completely satisfactory and adverse reactions can occur. Tripterygium glycosides (TG) is a promising component extracted from Tripterygium wilfordii Hook F (TwHF), and numerous patients with GO have benefited from it. However, its practical application value is still unclear. The aim of this systematic review and meta-analysis was to investigate the efficacy and safety of TG for patients with GO. METHODS: By retrieving the PubMed, Embase, the Cochrane Library, CNKI, VIP, CBM, and WanFang Databases, the open published randomized controlled trials (RCTs) related to TG in the treatment of GO were collected. And inclusion and exclusion criteria were established. The Cochrane bias risk assessment tool conducts the evaluation of included studies, and meta-analysis was performed using Revman 5.3 software. TRIAL REGISTRATION NUMBER: PROSPERO CRD42019131915. RESULTS: A total of 19 trials (involving 1517 GO patients) were included in this review with generally acceptable validity of included RCTs. TG therapy brought about a significantly higher efficacy rate compared with non-TG treatments (RR: 1.40; 95% CI: 1.31-1.49). Subgroup meta-analysis showed that TG with or without immunosuppressive therapies were all better than controls: with GC (RR: 1.36; 95% CI: 1.27-1.46), with multiple intensification of immunosuppressive therapies (RR: 1.91; 95% CI: 1.37-2.67), with no immunosuppressive therapies (RR: 1.39; 95% CI:1.21-1.59); the dosage of TG for 15-60 mg/d (RR: 1.41; 95% CI: 1.30-1.53) were better compared with for ≥90 mg/d (RR: 1.47; 95% CI: 1.29-1.68); the course of treatment for ≤3 months (RR: 1.43; 95% CI: 1.33-1.52) was better than controls, but when >3 months (RR: 1.15; 95% CI: 0.94-1.41) there was no significant differences. After treatment, the degree of exophthalmus (SMD: -2.55; 95% CI: -2.93 to 2.17), the recurrence rate of 1 year (RR: 0.45; 95% CI: 0.27-0.74), and adverse reactions rate (RR: 0.32; 95% CI: 0.20-0.53) were all lower, while the CAS was no obvious gap in 2 groups (SMD: 0.08; 95% CI: -0.60 to 0.75). CONCLUSIONS: This review found that TG has some advantages in treating GO, especially in improving clinical efficacy and reducing adverse reactions. Nevertheless, large sample, multi-center, reasonable design, and high quality clinical studies are still needed for further verification.

Influence of iodine on the reference interval of TSH and the optimal interval of TSH: results of a follow-up study in areas with different iodine intakes.

OBJECTIVE: The aim of the present study was to evaluate whether the status of iodine nutrition influences the TSH concentration in a selected Chinese reference population according to the criteria proposed by National Academy of Clinical Biochemistry (NACB) and regular thyroid ultrasonography, to establish a new reference interval of TSH based on the wide variation of iodine nutrition in populations, and to identify an optimal interval of TSH by following up the cohort with normal TSH concentrations at baseline. DESIGN: The study was conducted in Panshan, Zhangwu and Huanghua, the regions with mildly deficient, more than adequate and excessive iodine intake, respectively. Of the 3761 unselected subjects who were enrolled at baseline, 2237 met the criteria for a reference population. Of 3048 subjects with normal serum TSH at baseline, 2727 (80.0%) participated in the 5-year follow-up study. TSH and thyroid autoantibodies in serum and iodine in urine were measured, and B-mode ultrasonography of the thyroid was performed. RESULTS: In the reference population, there was a urinary iodine-related increment of serum TSH levels (r = 0.21, P = 0.000), and the mean levels of TSH in Panshan, Zhangwu and Huanghua were 1.15, 1.28 and 1.93 mIU/l, respectively (P = 0.000), corresponding to the rising regional iodine intake. Based on the overall data, we obtained a reference interval of 0.3-4.8 mIU/l. TSH concentrations obtained in the follow-up study correlated well with those at baseline (r = 0.58, P = 0.000). A baseline serum TSH > 1.9 mIU/l was associated with an increased incidence of development of supranormal TSH and a baseline serum TSH < 1.0 mIU/l was associated with an increased incidence of subnormal TSH development. CONCLUSIONS: Iodine nutrition is an important factor associated with TSH concentration even in the rigorously selected reference population. Baseline TSH of 1.0-1.9 mIU/l is an optimal interval with the lowest incidence of abnormal TSH in 5 years.